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 » Introduction
 »  Materials and Me...
 » Results
 » Discussion
 » Conclusion
 »  References
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 Table of Contents    
RESEARCH ARTICLE
Year : 2019  |  Volume : 51  |  Issue : 4  |  Page : 255-262
 

Low-dose sodium valproate versus low-dose propranolol in prophylaxis of common migraine headache: A randomized, prospective, parallel, open-label study


1 Department of Pharmacology, Government Medical College, Nagpur, Maharashtra, India
2 Department of Pharmacology, Indira Gandhi Government Medical College, Nagpur, Maharashtra, India

Date of Submission11-Feb-2019
Date of Acceptance18-Apr-2019
Date of Web Publication13-Sep-2019

Correspondence Address:
Dr. Vikas Sohanlal Sharma
201, Jagdish Ganga Apt., Hawrapeth, Rameshwari, Nagpur - 440 027, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_457_18

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 » Abstract 


CONTEXT: Migraine is the second most common headache disorder. However, prophylactic therapy remains underutilized.
AIMS: The objective of the study was to compare the efficacy and safety of low-dose sodium valproate and low-dose propranolol sustained release (SR) in the prophylaxis of common migraine headache.
SETTINGS AND DESIGN: The study was conducted in a tertiary care teaching institute. It was a randomized, prospective, parallel, open-label, clinical study.
SUBJECTS AND METHODS: The study included 60 patients with common migraine headaches (≥2 attacks/month) treated for 12 weeks. The patients were randomly divided into two treatment groups treated by sodium valproate 500 mg/day and propranolol SR 40 mg/day, respectively. The primary outcome measures were the percentage of responders (i.e., >50% decrease in mean headache frequency) at the end of 12 weeks and decrease in mean headache frequency (per 4 weeks) at the end of 12 weeks. The patients were assessed at 0, 4, 8, and 12 weeks of the study.
STATISTICAL ANALYSIS USED: Intention-to-treat analysis was used for all the statistical analysis.
RESULTS: Fifty-five patients completed the study. At the end of the treatment, both sodium valproate and propranolol caused a significant (P < 0.0001) reduction in frequency, severity, and duration of migraine headache. Propranolol caused significantly greater reduction in the severity of headache (P = 0.0410) than sodium valproate. The percentage of responders was 60% in sodium valproate group and 70% in propranolol group. Drowsiness was the most common adverse effect noted in both the groups.
CONCLUSION: Both sodium valproate and propranolol significantly reduced frequency, severity, and duration of migraine headache, but propranolol caused significantly greater reduction in the severity of headache compared to sodium valproate. Both the medications were well tolerated and did not result in discontinuation.


Keywords: Low dose, migraine headache, propranolol, sodium valproate


How to cite this article:
Dakhale GN, Sharma VS, Thakre MN, Kalikar M. Low-dose sodium valproate versus low-dose propranolol in prophylaxis of common migraine headache: A randomized, prospective, parallel, open-label study. Indian J Pharmacol 2019;51:255-62

How to cite this URL:
Dakhale GN, Sharma VS, Thakre MN, Kalikar M. Low-dose sodium valproate versus low-dose propranolol in prophylaxis of common migraine headache: A randomized, prospective, parallel, open-label study. Indian J Pharmacol [serial online] 2019 [cited 2019 Dec 15];51:255-62. Available from: http://www.ijp-online.com/text.asp?2019/51/4/255/266822





 » Introduction Top


Migraine headache is a common, universal, and incapacitating neurological disorder. The average prevalence of migraine is about 18% in women and 6% in men.[1],[2],[3] Majority of the patients with migraine require medication for the acute attack. Patients with an increased frequency of attacks (≥4/month, usually over 4–6 months) or with attacks that are either poorly responsive or unresponsive to acute treatments are ideal candidates for a prophylactic therapy, with the aim to reduce the frequency of attacks. The drugs approved for the prophylactic treatment of migraine headache include propranolol, sodium valproate, topiramate, flunarizine, and methysergide.[3] None of the available prophylactic agents are universally effective, and thus, the search continues to identify an agent with maximal efficacy and minimal adverse effect.

Propranolol is one of the most regularly used drugs for migraine prophylaxis with many clinical trials consistently proving its efficacy in reducing the frequency of migraine attacks.[4],[5],[6],[7] The prophylactically effective dose of propranolol ranges from 40 to 400 mg/day. The short-acting formulation can be given three to four times a day, and the long-acting formulation can be given once or twice a day.[8] Various studies have compared the efficacy of propranolol in different oral doses and with different drugs such as flunarizine, low-dose topiramate, and histamine.[4],[5],[6],[7],[9]

Efficacy of anticonvulsant drugs for migraine prophylaxis has been tested since long, with sodium valproate being the first drug approved from this group. Efficacy of sodium valproate in migraine prophylaxis has also been proven in many studies, where sodium valproate has been compared with different drugs in various doses.[10],[11],[12],[13],[14],[15] The prophylactically effective dose of sodium valproate ranges from 500 to 1500 mg/day.[8]

In spite of extensive literature search, we could not find any study comparing low-dose sodium valproate versus low-dose sustained release (SR) formulation of propranolol in the prophylaxis of migraine headache with reference to adult Indian population. If these low doses of sodium valproate and propranolol were actually effective in preventing migraine headache, it would imply a reduction in dose-dependent adverse effects as well as in the cost.

Thus, the present study was conducted with the objective of comparing the efficacy and safety of low-dose sodium valproate with low-dose SR formulation of propranolol in migraine prophylaxis.


 » Materials and Methods Top


This was a single-center, randomized, open-label, comparative, parallel-group study conducted in 60 newly diagnosed patients of common migraine headache, visiting the psychiatric outpatient department of a tertiary teaching institute over 18 months (February 2016–July 2017). The study was performed after approval of the Institutional Ethics Committee (EC/Pharmac/GMC/NGP/878). Informed consent was obtained from all the participants, and the study was registered in the Clinical Trial Registry of India (CTRI/2017/10/010241).

Selection criteria

Inclusion criteria

  1. Patients with a history of migraine without aura for at least 6 months before evaluation (as per International Classification of Headache Disorder definition [2.1.1])
  2. Patients experiencing 2–6 migraine attacks/month, but not ≥15 attacks/month
  3. Male or female patients in the age group of 18–60 years (both inclusive)
  4. Patients with a pain-free interval of at least 48 h in between two attacks
  5. Patients who were able to fill a headache diary successfully and reliably.


Exclusion criteria

  1. Patients having >15 migraine attacks/month or <2 migraine attacks/month
  2. Patients with a history of overuse or require rescue medication for acute migraine treatment for >10 treatment days/month or >3 days/week
  3. Patients had commenced any migraine prophylactic therapy within 1 month preceding the study
  4. Patient's headache attacks are associated with or attributable to an identifiable cause such as premenstrual period, disease of the eye, ear, or nose, and neurological disease or psychosis
  5. Patients with a known history of bronchial asthma, dyslipidemia, diabetes mellitus, uncontrolled hypertension, heart block, bradycardia, epilepsy, or other coexisting disease, for which they require a concomitant medication with antimigraine activity, such as β blocker, calcium channel blockers, antidepressants, or antiepileptics
  6. Women of child-bearing potential and men not willing to follow a reliable and effective birth control measure during the study and at least 3 months after the last visit
  7. Pregnant women or nursing mothers
  8. Patients who could not maintain a migraine diary, comply with the medication, or be regular in follow-up visits
  9. Patients with abnormal liver function test (LFT), kidney function test (KFT), random blood sugar (RBS), and lipid profile.


Study procedure

Migraine prophylactic therapy-naive patients who satisfied the selection criteria were included in the study. After initial screening, the baseline data regarding age, sex, weight, height, marital status, educational status, physical examination, clinical examination, and headache characteristics were recorded. Patients were randomized into Group A or Group B of 30 each in the ratio of 1:1. Group A received tablet sodium valproate 500 mg once daily for 12 weeks, and Group B received tablet propranolol SR 40 mg once daily for 12 weeks. In both the groups, the frequency of administration was increased to twice daily if there was no clinical improvement.

After allocating to their respective groups, body weight, pulse rate (PR), and blood pressure (BP) of the patients were recorded. RBS, lipid profile, KFT, and LFT were carried out as the screening and baseline investigations.

All the patients were asked to report every 4 weeks till 12 weeks for evaluation by a clinician. All the patients received respective medication for 4 weeks. At each subsequent visit, BP, PR, and body weight were recorded and the following details about migraine attack were obtained from the migraine diary as recorded by the patient – date and time of onset, time taken for relief of symptoms, distribution of headache, type of headache, frequency of attacks, severity of headache, associated symptoms, and use of rescue medication. The severity of headache was made from patients self-assessment migraine diary graded as mild = 1, moderate = 2, and severe = 3[10] (Mild – pain without consequence on normal activity; moderate – pain restricting normal activity without the need to go to bed; severe – pain preventing any activity and requires bed rest).

The results of the treatment were rated as follows: excellent, a reduction in the frequency of the migraine attacks by ≥50%; moderate, a reduction in the frequency of the migraine attacks by 49%–25%; and poor, a reduction in the frequency of the migraine attacks by <25%.[9]

Concomitant therapy

During the entire study, patients were allowed to use rescue medication for acute migraine attacks such as triptans or ergots and their combinations with nonsteroidal anti-inflammatory drugs (NSAIDs). Non-specific drugs such as antiemetics, simple analgesics like acetaminophen, and NSAIDs were also allowed during acute migraine attack.

Primary outcome measure

  1. Decrease in the mean frequency of migraine headache per 4 weeks
  2. The percentage of responders (patients for whom the frequency of headache decreased by ≥50% compared to baseline).


Secondary outcome measure

  1. Decrease in the mean severity of migraine headache per 4 weeks
  2. Decrease in the mean duration of migraine headache per 4 weeks.


Safety assessment

General clinical safety was monitored by vigilant follow-up of patients for the treatment-emergent adverse events (AEs), and baseline laboratory investigations were repeated at the 12th week.

Randomization

Random number table was used for random allocation of the study drugs. The randomized treatment allocation sequence was generated using a random number table.

Compliance with the study medication was determined by results of the interview at each patient visit, asking if they took the medication as prescribed and by direct pill count method.

Statistical analysis

Sample size calculation

Assuming the standard deviation of 1.8 and minimum clinically important difference of 1 in the mean monthly migraine frequency, between any two groups for 80% power and Type I error of 0.05, the required sample size turned out to be 27 patients in each group. Hence, to detect a clinically relevant difference between each group, 30 patients in each group were recruited considering the dropouts of 10%. The sample size was calculated using PS: Power and Sample Size Calculation software version 3.1.2 (by William D. Dupont and Walton D. Plummer, United States).

Efficacy and safety analysis

Intention-to-treat analysis was used for all the statistical analysis. Intergroup comparison of baseline parametric and nonparametric data was done by unpaired t-test and Fisher's exact test or Mann–Whitney test, respectively. Intragroup change in the parametric data and nonparametric data was compared at 0, 4, 8, and 12 weeks using repeated measures ANOVA and Friedman test, respectively, and post hoc analysis was performed by Bonferroni's multiple comparison test and Dunn's multiple comparison test, respectively. Percentage of responders and the occurrence of adverse drug events in the two groups were compared by Fisher's exact test. Results were expressed as absolute numbers and mean ± standard deviation, and P < 0.05 was considered statistically significant. The data was analyzed using PRISM version 5.01 (GraphPad Software, San Diego, California, USA).


 » Results Top


A total of 96 patients were screened and 60 patients were included, with 30 patients in each group. In sodium valproate group, two patients were lost to follow-up and one patient did not have adequate relief in headache and so was not willing to continue the treatment. In propranolol SR group, two patients were not willing to maintain the migraine diary and were excluded from the study. Thus, a total of 55 patients (27 in sodium valproate group and 28 in propranolol SR group) completed the 12-week study [Figure 1]. We have included all the 60 patients in our analysis under the intention-to-treat analysis.
Figure 1: Flowchart of the study

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In the present study, the baseline data showed no statistically significant difference between the study groups, with respect to demographic, clinical, and laboratory parameters, as well as headache characteristics [Table 1]. This proved the homogeneity of our study patients in the two groups. The mean age in sodium valproate group was 37.33 ± 9.79 years and in propranolol SR group was 33.83 ± 11.85 years. The percentage of female patients was relatively more than that of male patients, i.e., 73.33% in sodium valproate group and 63.33% in propranolol SR group.
Table 1: Baseline demographic, headache, and clinical parameters of two groups

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No significant change in body weight and diastolic BP was observed in both the groups, but significant change in PR (P< 0.0001) and systolic BP (P< 0.001) was observed only in propranolol SR group after the treatment [Table 2]. Statistically significant decrease in mean PR and systolic BP was observed after the treatment in propranolol SR group as compared to sodium valproate group. Furthermore, no significant decrease in mean weight and mean diastolic BP was observed between the two groups [Table 3].
Table 2: Change in clinical characteristics after 12 weeks of treatment

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Table 3: Difference between change in clinical characteristics in two groups

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Significant decrease in both frequency and severity (P< 0.0001) of migraine headache was observed after 4 weeks and maintained up to the end of the treatment in both the groups, whereas significant decrease in duration (P< 0.0001) of migraine headache was observed at 8 weeks and was further continued up to 12 weeks of treatment in both the groups [Table 4].
Table 4: Change in headache characteristics after 12 weeks of sodium valproate and propranolol sustained-release treatment

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Sodium valproate versus propranolol sustained-release group

Effects of drugs were evaluated after 4, 8, and 12 weeks of treatment, taking into consideration the change from baseline values in headache parameters. No significant difference in frequency and duration of migraine headache was seen after 4, 8, and 12 weeks of treatment in sodium valproate group compared to propranolol SR group, except in severity of migraine headache, where significant decrease occurred after 12 weeks of treatment in propranolol SR group (P = 0.0410) compared to sodium valproate group [Table 5]. Percentage (%) of responders at initial and increased dose showed no significant difference between the two groups in any of the ranges of percentage response [Table 6].
Table 5: Difference between change in headache characteristics in two groups

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Table 6: Comparison between groups: percentage responders at initial dose, increased dose, and final responders

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Overall, 10 (33.33%) patients reported one or more AEs in the sodium valproate and 8 (26.70%) in the propranolol SR group. Drowsiness and increased appetite were reported in 13.33% and 10.00% patients of the sodium valproate group, respectively, and in 10.00% and 6.67% patients of the propranolol SR group, respectively. Similarly, insomnia and vertigo were reported in 3.33% patients each of the sodium valproate group and in 10.00% and 3.33% patients of the propranolol SR group, respectively. Weight gain was seen in 10.00% of patients of sodium valproate group. Furthermore, decreased appetite and increased headache were seen in 3.33% patients each in propranolol SR group. Transient AEs such as mouth ulcers and paresthesia over both hands and feet were seen in 3.33% patients each in sodium valproate group only. There was no significant difference in RBS, lipid profile, KFT, and LFT after 12 weeks of treatment in both the groups.


 » Discussion Top


The principal finding of our study indicates that both low-dose sodium valproate and low-dose SR formulation of propranolol significantly decreased the frequency, severity, and duration of headache.

Maximum decrease in frequency, severity, and duration of migraine headache in both the groups occurred at visit 2 (4 weeks), indicating a similar onset of action and rate of symptomatic improvement. During the subsequent visit, there was a gradual further decrease in the headache parameters, indicating that the improvement was sustained throughout the study without loss of efficacy. None of the available studies compared the time of onset of sodium valproate and propranolol SR.

In sodium valproate group, there was a significant decrease in frequency, severity, and duration of migraine headache. Similar finding was observed in other studies.[10],[11],[12],[13],[14] The mechanism of action of sodium valproate in migraine prophylaxis is not fully agreed upon although indirect increase in Gamma-aminobutyric acid (GABA) activity is involved. Proposed antinociceptive activity at the trigeminal nucleus caudalis includes increasing presynaptic GABA levels in synaptosomes by inhibition of GABA aminotransferase, increasing the response to GABA postsynaptically, and inhibition of neurogenic inflammation through GABAA potentiation.[16]

Similarly, in propranolol SR group, there was a significant decrease in frequency, severity, and duration of migraine headache. Carroll et al., Diener et al., and others reported similar findings.[4],[5],[6],[7],[17] The mechanisms of action of propranolol in migraine prophylaxis are not fully understood; it is proposed that propranolol reduces central hyperexcitability through β1-mediated inhibition of noradrenaline release, thus reducing central catecholaminergic hyperactivity, and enhances antinociception, antagonism of 5-HT1A and 5-HT2B receptors, which decreases neuronal excitability, and β2-mediated inhibition of nitric oxide (NO) synthesis by blocking inducible NO synthase.[16]

The percentage of responders was 60% in sodium valproate group and 70% in propranolol SR group. Furthermore, it was observed that only a third and less than one-fourth of patients required higher doses of sodium valproate and propranolol, respectively, in controlling migraine attacks.

Low doses of sodium valproate have also been found to be effective by Afshari et al. in a clinical trial comparing low-dose topiramate and sodium valproate.[11] A significant decrease in monthly frequency, duration, and intensity of headache occurred in both the groups. Similarly, low-dose sodium valproate has been compared with cinnarizine and levetiracetam in different studies.[12],[13]

Propranolol was tried in different doses for migraine prophylaxis in a clinical study, and low dose was found to be equally efficacious in reducing frequency and duration of headache.[18] Low doses of propranolol have also been found to be effective by Ashtari et al. and Cortelli et al.[6],[18] Various studies have compared slow release propranolol and single dose of propranolol with other drugs such as flunarizine and candesartan.[5],[17]

There was no significant difference in frequency and duration of migraine headache in between sodium valproate and propranolol SR group. However, there was statistically significant decrease in the severity of migraine headache in propranolol SR group compared to sodium valproate group at the end of the study. Furthermore, there was no significant difference in percentage of responders in between sodium valproate and propranolol SR group at the end of the study. Only one study is available, comparing the efficacy of sodium valproate with propranolol in the prophylaxis of migraine headache in the adult population but with different dose strength and for different treatment duration.[15] Similar results were obtained in our study although at much lower doses.

The secondary objectives of our study were to assess the adverse drug profile of sodium valproate and propranolol SR in the patients of common migraine headache. We found that, at the end of the treatment period, RBS, lipid profile, LFT, and KFT were within normal limits in both the treatment groups and intergroup analysis revealed no significant difference in any of these parameters. None of the available studies monitored RBS, lipid profile, and KFT in patients treated with sodium valproate. However, some of the available studies monitored LFT and found no significant change.[11],[12],[14],[19] Furthermore, none of the available studies monitored RBS, lipid profile, KFT, and LFT in patients treated with propranolol. Sodium valproate is known to raise the levels of serum transaminases, and propranolol is known to increase plasma triglyceride level and low-density lipoprotein/high-density lipoprotein ratio, but we did not find any such altered values.[20] This may be because of the low doses used in this study.

In sodium valproate group, there was no significant change in PR, BP, and weight at the end of the study. Similar findings are reported by Afshari et al. and Togha et al.[11],[19] In propranolol SR group, there was a significant decrease in PR and systolic BP and no significant change in diastolic BP and weight at the end of the treatment period. Similarly, significant decrease in PR and systolic BP was reported by Diener et al.[5] and Gawel et al.,[21] and no significant change in weight was reported by Tfelt-Hansen et al.[22] and Cortelli et al.[18]

Intergroup analysis revealed significant change in PR and systolic BP and no significant change in weight and diastolic BP at the end of the treatment period in propranolol SR group as compared to sodium valproate group. Decrease in systolic BP and PR during the treatment period although significant was only moderate and did not necessitate any withdrawal of treatment.

AEs were noted in ten patients receiving sodium valproate and eight patients receiving propranolol SR. Drowsiness was the most common AE in both the groups. Most of the AEs noted in our study have been reported in earlier studies such as drowsiness, increased appetite, weight gain, insomnia, and vertigo in sodium valproate group[10],[11],[12],[23] and insomnia, drowsiness, increased headache, and vertigo in propranolol SR group.[4],[5],[24] AE rate was more in sodium valproate group as compared to propranolol SR group but did not lead to drug discontinuation.

Limitations

Limitations included open-label nature of the study, and the protocol did not allow a further increase in dose in patients with inadequate response. Further, elaborate multicentric studies involving a larger number of patients, with different comorbidities and risk factors, and receiving different concomitant medications, with a longer duration of prophylactic therapy may be undertaken to generate more efficacy data regarding the relative efficacy and tolerability of these low-dose medications.


 » Conclusion Top


Both low-dose sodium valproate and low-dose SR formulation of propranolol significantly decreased the frequency, severity, and duration of migraine headache. Low-dose SR formulation of propranolol offers a significant decrease in the severity of migraine headache compared to low-dose sodium valproate. Sixty percent of patients were responders in sodium valproate group and 70% in propranolol SR group. In addition to confirming the well-known utility of both sodium valproate and propranolol in migraine prophylaxis, our results show that low doses are effective in controlling serious migraine attacks in many patients.

Acknowledgment

We are thankful to the staff of Department of Psychiatry for the support provided.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1545-602.  Back to cited text no. 1
    
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Stovner LJ, Hagen K, Jensen R, Katsarava Z, Lipton R, Scher A, et al. The global burden of headache: A documentation of headache prevalence and disability worldwide. Cephalalgia 2007;27:193-210.  Back to cited text no. 2
    
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Goadsby PJ, Raskin NH. Migraine and other primary headache disorders. Harrisons' Principles of Internal Medicine. 19th ed., Ch. 447. New Delhi: McGraw-Hill Companies, Inc.; 2015. p. 2586-94.  Back to cited text no. 3
    
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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;10:101-5.  Back to cited text no. 4
    
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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;22:209-21.  Back to cited text no. 5
    
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Ashtari F, Shaygannejad V, Akbari M. A double-blind, randomized trial of low-dose topiramate vs. propranolol in migraine prophylaxis. Acta Neurol Scand 2008;118:301-5.  Back to cited text no. 6
    
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Millán-Guerrero RO, Isais-Millán R, Guzmán-Chávez B, Castillo-Varela G. N alpha methyl histamine versus propranolol in migraine prophylaxis. Can J Neurol Sci 2014;41:233-8.  Back to cited text no. 7
    
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Silberstein SD. Preventive migraine treatment. Neurol Clin 2009;27:429-43.  Back to cited text no. 8
    
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Afshari D, Rafizadeh S, Rezaei M. A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis. Int J Neurosci 2012;122:60-8.  Back to cited text no. 11
    
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Bostani A, Rajabi A, Moradian N, Razazian N, Rezaei M. The effects of cinnarizine versus sodium valproate in migraine prophylaxis. Int J Neurosci 2013;123:487-93.  Back to cited text no. 12
    
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Sadeghian H, Motiei-Langroudi R. Comparison of levetiracetam and sodium valproate in migraine prophylaxis: A randomized placebo-controlled study. Ann Indian Acad Neurol 2015;18:45-8.  Back to cited text no. 13
[PUBMED]  [Full text]  
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Rahimdel A, Zeinali A, Yazdian-Anari P, Hajizadeh R, Arefnia E. Effectiveness of Vitamin B2 versus sodium valproate in migraine prophylaxis: A randomized clinical trial. Electron Physician 2015;7:1344-8.  Back to cited text no. 14
    
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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 2014;34:523-32.  Back to cited text no. 17
    
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Cortelli P, Sacquegna T, Albani F, Baldrati A, D'Alessandro R, Baruzzi A, et al. Propranolol plasma levels and relief of migraine. Relationship between plasma propranolol and 4-hydroxypropranolol concentrations and clinical effects. Arch Neurol 1985;42:46-8.  Back to cited text no. 18
    
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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;69:1-8.  Back to cited text no. 22
    
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Takeshima T, Suzuki N, Matsumori Y, Shimmoto N, Kurihara Y, Gunji R, et al. Effectiveness and safety of an extended-release tablet of sodium valproate for the prophylactic treatment of migraine: Postmarketing surveillance in Japan. Neurol Clin Neurosci 2016;4:134-41.  Back to cited text no. 23
    
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Domingues RB, Silva AL, Domingues SA, Aquino CC, Kuster GW. A double-blind randomized controlled trial of low doses of propranolol, nortriptyline, and the combination of propranolol and nortriptyline for the preventive treatment of migraine. Arq Neuropsiquiatr 2009;67:973-7.  Back to cited text no. 24
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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