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.
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.
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.
Citation: Jackson JL, Cogbill E, Santana-Davila R, Eldredge C, Collier W, Gradall A, et al. (2015) A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache. PLoS ONE 10(7): e0130733. https://doi.org/10.1371/journal.pone.0130733
Editor: Oscar Arias-Carrion, Hospital General Dr. Manuel Gea González, MEXICO
Received: May 18, 2014; Accepted: May 24, 2015; Published: July 14, 2015
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication
Data Availability: Relevant data are available on figshare.com: (http://dx.doi.org/10.6084/m9.figshare.1431538).
Funding: The authors have no support or funding to report.
Competing interests: The authors have declared that no competing interests exist.
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 , 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 . 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.
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 , beta-blockers , botulinum-A , calcium channel blockers , serotonin agonists, serotonin reuptake inhibitors (SSRIs)  and tricyclic antidepressants (TCAs) . 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 . 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 . 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 . 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 . 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 . 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.
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 . 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 . When missing, variances were calculated from reported mean, sample size and p values ; for one non-placebo comparison trial  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 . 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  and the Jadad scale  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% . 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 . 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  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 , and I-square .We assessed for small study effects (publication bias) using the methods of Peters  for dichotomous outcomes and Eggers  for continuous ones. We explored the potential source of heterogeneity using stratified analysis and random-effects meta-regression . 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.
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 , 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].
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.
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).
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.
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.
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 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 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).
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.
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).
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.
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).
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).
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).
Network meta-analysis and direct comparisons found no difference in likelihood of experiencing “any” side effect or in the rate of withdrawing from studies.
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.
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 . 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 . While our findings are similar to previous reviews of anticonvulsants , the beta-blocker propranolol , anticonvulsants  and tricyclic antidepressants , we found some important differences. Anticonvulsants were less effective than a 2004 Cochrane review, 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 inappropriately pooled both migraine and tension headaches together. Our 1996 review  also combined migraine and tension headaches, likely inappropriate given potentially important pathophysiologic differences. A 2005 Cochrane review of SSRIs found no benefit, 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 .
A recent systematic review examined the efficacy of prophylactic treatment for episodic migraine headaches 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.
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.
Conceived and designed the experiments: JLJ EC RSD CE WC AG NS JK. Performed the experiments: JLJ EC RSD CE WC AG NS JK. Analyzed the data: JLJ EC RSD. Contributed reagents/materials/analysis tools: JLJ EC RSD CE WC AG NS JK. Wrote the paper: JLJ EC RSD CE WC AG NS JK.
- 1. Rasmussen BK (2001) Epidemiology of headache. Cephalalgia 21: 774–777. pmid:11595011
- 2. Wang SJ (2003) Epidemiology of migraine and other types of headache in Asia. Current Neurology & Neuroscience Reports 3: 104–108.
- 3. Radtke A, Neuhauser H (2009) Prevalence and burden of headache and migraine in Germany. Headache 49: 79–89. HED1263 [pii]; pmid:19125877
- 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. pmid:16538424
- 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]. pmid:21243244
- 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. pmid:12807522
- 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]. pmid:12807523
- 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]; pmid:20813784
- 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. pmid:21029083
- 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.
- 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]; pmid:18471125
- 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]; pmid:17697913
- 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. pmid:10219926
- 14. Goldberg LD (2005) The cost of migraine and its treatment. Am J Manag Care 11: S62–S67. 2883 [pii]. pmid:16095269
- 15. (2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33: 629–808. pmid:23771276
- 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];
- 17. Law S, Derry S, Moore RA (2010) Triptans for acute cluster headache. Cochrane Database Syst Rev CD008042.
- 18. McCrory DC, Gray RN (2003) Oral sumatriptan for acute migraine. Cochrane Database Syst Rev CD002915.
- 19. Chronicle E, Mulleners W (2004) Anticonvulsant drugs for migraine prophylaxis. Cochrane Library.
- 20. Linde K, Rossnagel K (2004) Propranolol for migraine prophylaxis. Cochrane Database Syst Rev CD003225. 10.1002/14651858.CD003225.pub2.
- 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]; pmid:22535858
- 22. Pringsheim T, Davenport WJ, Becker WJ (2010) Prophylaxis of migraine headache. CMAJ 182: E269–E276. cmaj.081657 [pii]; pmid:20159899
- 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. pmid:4867512
- 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.
- 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. pmid:20961988
- 26. Rapaport AM (1994) Recurrent migraine: cost-effective care. Neurology 44: S25–S28. pmid:8202231
- 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]; pmid:22529202
- 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. pmid:23592242
- 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. pmid:19621072
- 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.
- 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.
- 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]; pmid:18294250
- 33. Kazis LE, Anderson JJ, Meenan RF (1989) Effect sizes for interpreting changes in health status. Med Care 27: S178–S189. pmid:2646488
- 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]. pmid:1619456
- 35. Hubbe P (1973) The prophylactic treatment of migraine with an antiserotonin pizotifen. Acta Neurol Scand 49: 108–114. pmid:4567747
- 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. pmid:17652297
- 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]; pmid:19907043
- 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.
- 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. pmid:8721797
- 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]. pmid:3802833
- 43. Mathew NT (2001) Antiepileptic drugs in migraine prevention. Headache 41 Suppl 1: S18–S24. 01154–4 [pii]. pmid:11903536
- 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. pmid:20825617
- 45. Lumley T (2002) Network meta-analysis for indirect treatment comparisons. Stat Med 21: 2313–2324. pmid:12210616
- 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. pmid:20688472
- 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. pmid:20537177
- 48. Galbraith RF (1988) A note on graphical presentation of estimated odds ratios from several clinical trials. Statistics in Medicine 7: 889–894. pmid:3413368
- 49. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327: 557–560. 327/7414/557 [pii]. pmid:12958120
- 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]; pmid:16467236
- 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. pmid:9310563
- 52. Sharp S (1998) Meta-analysis regression. Stata Technical Bulletin 42: 16–22.
- 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. pmid:368333
- 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. pmid:367043
- 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. pmid:2666565
- 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. pmid:1094661
- 57. Mondrup K, Moller CE (1977) Prophylactic treatment of migraine with clonidine. A controlled clinical trial. Acta Neurol Scand 56: 405–412. pmid:339659
- 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. pmid:1100565
- 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]. pmid:12167135
- 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. pmid:4110641
- 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. pmid:773082
- 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. pmid:1493669
- 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. pmid:11141144
- 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. pmid:23413003
- 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]; pmid:19250283
- 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];
- 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]. pmid:12503978
- 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]; pmid:21059626
- 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. 291/8/965 [pii]. pmid:14982912
- 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]; pmid:19222595
- 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]; pmid:17709295
- 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. pmid:10958046
- 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. pmid:15316798
- 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]; pmid:17441971
- 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. pmid:12858132
- 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. pmid:12058094
- 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]. pmid:9658386
- 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]; pmid:16494657
- 79. Hering R, Kuritzky A (1992) Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia 12: 81–84. pmid:1576648
- 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. pmid:8164818
- 81. Klapper J (1997) Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 17: 103–108. pmid:9137847
- 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]; pmid:20974598
- 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. pmid:7872882
- 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. 00002826-200609000-00005 [pii]. pmid:16960472
- 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. pmid:4905910
- 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]; pmid:24862255
- 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. 61/4/490 [pii]. pmid:15096395
- 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]; pmid:16990078
- 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]; pmid:17300356
- 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]; pmid:18268247
- 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]; pmid:23165696
- 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]. pmid:14510929
- 93. Spira PJ, Beran RG (2003) Gabapentin in the prophylaxis of chronic daily headache: a randomized, placebo-controlled study. Neurology 61: 1753–1759. pmid:14694042
- 94. Steiner TJ, Findley LJ, Yuen AW (1997) Lamotrigine versus placebo in the prophylaxis of migraine with and without aura. Cephalalgia 17: 109–112. pmid:9137848
- 95. Stensrud P, Sjaastad O (1979) Clonazepam (rivotril) in migraine prophylaxis. Headache 19: 333–334. pmid:511533
- 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]. pmid:11903524
- 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. pmid:11985388
- 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. pmid:24201237
- 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. pmid:18231713
- 100. Ahuja GK, Verma AK (1985) Propranolol in prophylaxis of migraine. Indian J Med Res 82: 263–265. pmid:3908306
- 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. pmid:8495455
- 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. pmid:6640652
- 103. Borgesen SE, Nielsen JL, Moller CE (1974) Prophylactic treatment of migraine with propranolol. A clinical trial. Acta Neurol Scand 50: 651–656. pmid:4611129
- 104. Briggs RS, Millac PA (1979) Timolol in migraine prophylaxis. Headache 19: 379–381. pmid:511540
- 105. Dahlof C (1987) No clearcut longterm prophylactic effect of one month of treatment with propranolol in migraineurs. Cephalalgia 7: 459–460.
- 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. pmid:8902255
- 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. pmid:4402287
- 108. Ekbom K (1975) Alprenolol for migraine prophylaxis. Headache 15: 129–132. pmid:1097368
- 109. Ekbom K, Zetterman M (1977) Oxprenolol in the treatment of migraine. Acta Neurol Scand 56: 181–184. pmid:331835
- 110. Forssman B, Henriksson KG, Johannsson V, Lindvall L, Lundin H (1976) Propranolol for migraine prophylaxis. Headache 16: 238–245. pmid:977330
- 111. Forssman B, Lindblad CJ, Zbornikova V (1983) Atenolol for migraine prophylaxis. Headache 23: 188–190. pmid:6350226
- 112. Freitag FG, Diamond S (1984) Nadolol and placebo comparison study in the prophylactic treatment of migraine. J Am Osteopath Assoc 84: 343–347. pmid:6150909
- 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. pmid:20880898
- 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. pmid:3308768
- 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. pmid:3524092
- 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. pmid:6428749
- 117. Malvea BP, Gwon N, Graham JR (1973) Propranolol prophylaxis of migraine. Headache 12: 163–167. pmid:4566216
- 118. Mathew NT (1981) Prophylaxis of migraine and mixed headache. A randomized controlled study. Headache 21: 105–109. pmid:7021472
- 119. Mikkelsen B, Pedersen KK, Christiansen LV (1986) Prophylactic treatment of migraine with tolfenamic acid, propranolol and placebo. Acta Neurol Scand 73: 423–427. pmid:3727918
- 120. Nadelmann JW, Phil M, Stevens J, Saper JR (1986) Propranolol in the prophylaxis of migraine. Headache 26: 175–182. pmid:3519529
- 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. pmid:348644
- 122. Palferman TG, Gibberd FB, Simmonds JP (1983) Prophylactic propranolol in the treatment of headache. Br J Clin Pract 37: 28–29. pmid:6340710
- 123. Pita E, Higueras A, Bolanos J, Perez N, Mundo A (1977) Propranolol and migraine. A clinical trial. Arch Farmacol Toxicol 3: 273–278. pmid:350168
- 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. pmid:2692838
- 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. pmid:3902723
- 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. pmid:4401692
- 127. Standnes B (1982) The prophylactic effect of timolol versus propranolol and placebo in common migraine: beta-blockers in migraine. Cephalalgia 2: 165–170. pmid:6758949
- 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. pmid:3277926
- 129. Stellar S, Ahrens SP, Meibohm AR, Reines SA (1984) Migraine prevention with timolol. A double-blind crossover study. JAMA 252: 2576–2580. pmid:6387197
- 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. pmid:773081
- 131. Stensrud P, Sjaastad O (1980) Comparative trial of Tenormin (atenolol) and Inderal (propranolol) in migraine. Headache 20: 204–207. pmid:6993420
- 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. pmid:6367336
- 133. van de Ven LL, Franke CL, Koehler PJ (1997) Prophylactic treatment of migraine with bisoprolol: a placebo-controlled study. Cephalalgia 17: 596–599. pmid:9251876
- 134. Weber RB, Reinmuth OM (1972) The treatment of migraine with propranolol. Neurology 22: 366–369. pmid:4552716
- 135. Wideroe TE, Vigander T (1974) Propranolol in the treatment of migraine. Br Med J 2: 699–701. pmid:4604977
- 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. pmid:3579659
- 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.
- 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.
- 139. Ansell E, Fazzone T, Festenstein R, Johnson ES, Thavapalan M, Wilkinson M, et al. (1988) Nimodipine in migraine prophylaxis. Cephalalgia 8: 269–272. pmid:3064919
- 140. Gelmers HJ (1983) Nimodipine, a new calcium antagonist, in the prophylactic treatment of migraine. Headache 23: 106–109. pmid:6347970
- 141. Havanka-Kanniainen H, Hokkanen E, Myllyla VV (1985) Efficacy of nimodipine in the prophylaxis of migraine. Cephalalgia 5: 39–43. pmid:3886153
- 142. Leandri M, Rigardo S, Schizzi R, Parodi CI (1990) Migraine treatment with nicardipine. Cephalalgia 10: 111–116. pmid:2245455
- 143. Markley HG, Cheronis JC, Piepho RW (1984) Verapamil in prophylactic therapy of migraine. Neurology 34: 973–976. pmid:6539877
- 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. pmid:2644581
- 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. pmid:8773038
- 146. Solomon GD, Steel JG, Spaccavento LJ (1983) Verapamil prophylaxis of migraine. A double-blind, placebo-controlled study. JAMA 250: 2500–2502. pmid:6355533
- 147. Stewart DJ, Gelston A, Hakim A (1988) Effect of prophylactic administration of nimodipine in patients with migraine. Headache 28: 260–262. pmid:3170182
- 148. Diamond S, Freitag FG (1992) A double-blind trial of flunarizine in migraine prophylaxis. Headache Quarterly 4: 169–172.
- 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]. pmid:6325065
- 150. Louis P (1981) A double-blind placebo-controlled prophylactic study of flunarizine (Sibelium) in migraine. Headache 21: 235–239. pmid:7031016
- 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. pmid:3886152
- 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. pmid:3957502
- 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.
- 154. Thomas M, Behari M, Ahuja GK (1991) Flunarizine in migraine prophylaxis: an Indian trial. Headache 31: 613–615. pmid:1774179
- 155. Adly C, Straumanis J, Chesson A (1992) Fluoxetine prophylaxis of migraine. Headache 32: 101–104. pmid:1551787
- 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. pmid:11279947
- 157. Landy S, McGinnis J, Curlin D, Laizure SC (1999) Selective serotonin reuptake inhibitors for migraine prophylaxis. Headache 39: 28–32. HEDhed3901028 [pii]; pmid:15613191
- 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. pmid:8002320
- 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. pmid:9673809
- 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. pmid:6753446
- 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]; pmid:15705120
- 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. pmid:4925988
- 163. Bellavance AJ, Meloche JP (1990) A comparative study of naproxen sodium, pizotyline and placebo in migraine prophylaxis. Headache 30: 710–715. pmid:2074163
- 164. Carroll JD, Maclay WP (1975) Pizotifen (BC 105) in migraine prophylaxis. Curr Med Res Opin 3: 68–71. pmid:1095308
- 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. pmid:9252796
- 166. Hughes RC, Foster JB (1971) BC 105 in the prophylaxis of migraine. Curr Ther Res Clin Exp 13: 63–68. pmid:4992568
- 167. Kangasniemi P (1979) Placebo, 1-isopropylnoradrenochrome-5-monosemicarbazono and pizotifen in migraine prophylaxis. Headache 19: 219–222. pmid:156165
- 168. Lawrence ER, Hossain M, Littlestone W (1977) Sanomigran for migraine prophylaxis, controlled multicenter trial in general practice. Headache 17: 109–112. pmid:330465
- 169. Osterman PO (1977) A comparison between placebo, pizotifen and 1-isopropyl-3-hydroxy-5-semicarbazono-6-oxo-188.8.131.52-tetrahydroindol (Divascan) in migraine prophylaxis. Acta Neurol Scand 56: 17–28. pmid:327746
- 170. Ryan RE (1968) Double-blind crossover comparison of bc-105, methysergide and placebo in the prophylaxis of migraine headache. Headache 8: 118–126. pmid:4892617
- 171. Couch JR, Hassanein RS (1979) Amitriptyline in migraine prophylaxis. Arch Neurol 36: 695–699. pmid:508127
- 172. Couch JR (2011) Amitriptyline in the prophylactic treatment of migraine and chronic daily headache. Headache 51: 33–51. pmid:21070231
- 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. pmid:4731336
- 174. Jacobs H (1972) A trial of opipramol in the treatment of migraine. J Neurol Neurosurg Psychiatry 35: 500–504. pmid:4559028
- 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. pmid:3886599
- 176. Morland TJ, Storli OV, Mogstad TE (1979) Doxepin in the prophylactic treatment of mixed 'vascular' and tension headache. Headache 19: 382–383. pmid:511541
- 177. Noone JF (1980) Clomipramine in the prevention of migraine. J Int Med Res 8 Suppl 3: 49–52. pmid:7009254
- 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. pmid:6998250
- 179. Louis P, Schoenen J, Hedman C (1985) Metoprolol v. clonidine in the prophylactic treatment of migraine. Cephalalgia 5: 159–165.
- 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. pmid:21950578
- 181. Albers GW, Simon LT, Hamik A, Peroutka SJ (1989) Nifedipine versus propranolol for the initial prophylaxis of migraine. Headache 29: 215–218. pmid:2654067
- 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. pmid:10983362
- 183. Andersson PG (1973) BC-105 and deseril in migraine prophylaxis. (A double-blind study). Headache 13: 71–73. pmid:4578493
- 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. pmid:7032183
- 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]; pmid:18713156
- 186. Bank J (1994) A comparative study of amitriptyline and fluvoxamine in migraine prophylaxis. Headache 34: 476–478. pmid:7960733
- 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]. pmid:16340383
- 188. Behan PO, Connelly K (1986) Prophylaxis of migraine: a comparison between naproxen sodium and pizotifen. Headache 26: 237–239. pmid:3522482
- 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. pmid:9818888
- 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. pmid:9629401
- 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. pmid:23311688
- 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]; pmid:15567552
- 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. pmid:22188311
- 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.
- 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]. pmid:12047461
- 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]; pmid:19393844
- 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]. pmid:20069203
- 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. pmid:1782981
- 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. pmid:4556413
- 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. pmid:1393843
- 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. pmid:2036669
- 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]; pmid:17371357
- 203. Hubbe P (1973) The prophylactic treatment of migraine with an antiserotonin pizotifen. Acta Neurol Scand 49: 108–114. pmid:4567747
- 204. Kalita J, Bhoi SK, Misra UK (2013) Amitriptyline vs divalproate in migraine prophylaxis: a randomized controlled trial. Acta Neurol Scand 128: 65–72. pmid:23406477
- 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. pmid:6606930
- 206. Kaniecki RG (1997) A comparison of divalproex with propranolol and placebo for the prophylaxis of migraine without aura. Arch Neurol 54: 1141–1145. pmid:9311358
- 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]; pmid:18620801
- 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]. pmid:12167139
- 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. pmid:22008899
- 210. Louis P, Spierings EL (1982) Comparison of flunarizine (Sibelium) and pizotifen (Sandomigran) in migraine treatment: a double-blind study. Cephalalgia 2: 197–203. pmid:6760980
- 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. pmid:3180198
- 212. Ludin HP (1989) Flunarizine and propranolol in the treatment of migraine. Headache 29: 219–224. pmid:2654068
- 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. pmid:22233396
- 214. Mitsikostas DD, Polychronidis I (1997) Valproate versus flunarizine in migraine prophylaxis: a randomized, double-open, clinical trial. Funct Neurol 12: 267–276. pmid:9439944
- 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. pmid:21738025
- 216. Olerud B, Gustavsson CL, Furberg B (1986) Nadolol and propranolol in migraine management. Headache 26: 490–493. pmid:3546194
- 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. pmid:6391066
- 218. Presthus J (1971) BC 105 and methysergide (Deseril) in migraine prophylaxis. Acta Neurol Scand 47: 514–518. pmid:4941732
- 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]; pmid:15539864
- 220. Rascol A, Montastruc JL, Rascol O (1986) Flunarizine versus pizotifen: a double-blind study in the prophylaxis of migraine. Headache 26: 83–85. pmid:3514549
- 221. Ryan RE Sr (1984) Comparative study of nadolol and propranolol in prophylactic treatment of migraine. Am Heart J 108: 1156–1159. pmid:6148878
- 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.
- 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]; pmid:16643559
- 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. pmid:2404346
- 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. pmid:1769820
- 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. pmid:3312113
- 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.
- 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. pmid:18286231
- 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.
- 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. pmid:23865122
- 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. pmid:7714010
- 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. pmid:1376839
- 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. pmid:23358935
- 234. Chronicle E, Mulleners W (2004) Anticonvulsant drugs for migraine prophylaxis. Cochrane Database Syst Rev CD003226.
- 235. Linde K, Rossnagel K (2004) Propranolol for migraine prophylaxis. Cochrane Database Syst Rev CD003225.
- 236. Mulleners WM, McCrory DC, Linde M (2014) Antiepileptics in migraine prophylaxis: An updated Cochrane review. Cephalalgia. 0333102414534325 [pii];
- 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. pmid:20961988
- 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]. pmid:11448661
- 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.
- 240. Pringsheim T, Davenport WJ, Becker WJ (2010) Prophylaxis of migraine headache. CMAJ 182: E269–E276. cmaj.081657 [pii]; pmid:20159899
- 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. pmid:943066
- 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. pmid:5554982