Skip to main content

Advertisement

SpringerLink
Log in

Levetiracetam as preventive treatment in adults with migraine: an up-to-date systematic review and quantitative meta-analysis

  • Review
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The aim of this systematic review was to evaluate current evidence on the efficacy and safety of levetiracetam as migraine prophylaxis in adult patients suffering from migraine attacks.

Methods

PubMed, Scopus, Cochrane Central Register of Controlled Trials, and International Web of Science were searched (last search in August 2018) for studies investigating levetiracetam for migraine prophylaxis in adults. Both randomized and non-randomized trials were eligible. Efficacy was the primary outcome, but tolerability was also investigated. The study is registered on PROSPERO, number CRD42018088900.

Results

Nine studies, enrolling 215 patients, were included. Levetiracetam decreased the frequency of attacks with headache in all studies, with a pooled mean difference of −3.02 (95% CI: −4.59 to −1.45; I2 = 0%), −4.65(−7 to −2.3; I2 = 0%), and −5.71 (−8.60 to −2.82; I2 = 0%) at 1, 3, and 6 months compared with baseline. Three randomized controlled trials were included, and levetiracetam was superior to placebo in two but was inferior to sodium valproate in reducing headache frequency. Similar results were found in the other indices of efficacy, and levetiracetam was generally well tolerated.

Conclusion

Levetiracetam may be a relatively safe and efficacious treatment for the prophylaxis of migraine based on limited evidence, most from uncontrolled studies. Further evidence from randomized controlled trials is necessary.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Steiner TJ, Stovner LJ, Vos T, Jensen R, Katsarava Z (2018) Migraine is first cause of disability in under 50s: will health politicians now take notice? J Headache Pain 19(1):17

    Article  Google Scholar 

  2. IHS (2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. (1468–2982 (Electronic))

  3. Sprenger T, Goadsby PJJBM (2009) Migraine pathogenesis and state of pharmacological treatment options 7(1):71

  4. 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

    Article  Google Scholar 

  5. Goadsby PJ, Sprenger T (2010) Current practice and future directions in the prevention and acute management of migraine. Lancet Neurol 9(3):285–298

    Article  Google Scholar 

  6. Evers S, Afra J, Frese A, Goadsby PJ, Linde M, May A et al (2009) EFNS guideline on the drug treatment of migraine—revised report of an EFNS task force. Eur J Neurol 16(9):968–981

    Article  CAS  Google Scholar 

  7. Welch KM, D’Andrea G, Tepley N, Barkley G, Ramadan NM (1990) The concept of migraine as a state of central neuronal hyperexcitability. Neurol Clin 8(4):817–828

    Article  CAS  Google Scholar 

  8. Apostol G, Lewis DW, Laforet GA, Robieson WZ, Fugate JM, Abi-Saab WM et al (2009) Divalproex sodium extended-release for the prophylaxis of migraine headache in adolescents: results of a stand-alone, long-term open-label safety study. Headache. 49(1):45–53

    Article  Google Scholar 

  9. 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(8):965–973

    Article  CAS  Google Scholar 

  10. Niespodziany I, Klitgaard H, Margineanu DG (2001) Levetiracetam inhibits the high-voltage-activated Ca(2+) current in pyramidal neurones of rat hippocampal slices. Neurosci Lett 306(1–2):5–8

    Article  CAS  Google Scholar 

  11. Lukyanetz EA, Shkryl VM, Kostyuk PG (2002) Selective blockade of N-type calcium channels by levetiracetam. Epilepsia. 43(1):9–18

    Article  CAS  Google Scholar 

  12. Patsalos PN (2003) The pharmacokinetic characteristics of levetiracetam. Methods Find Exp Clin Pharmacol 25(2):123–129

    Article  CAS  Google Scholar 

  13. Haria M, Balfour JA (1997) Levetiracetam. CNS Drugs 7(2):159–164

    Article  CAS  Google Scholar 

  14. Pizza V, Busillo V, Agresta A, Bisogno A, Capasso A (2011) Elderly patients with migraine: an open-label study on prophylaxis therapy with levetiracetam. Cent Nerv Syst Agents Med Chem 11(1):31–34

    Article  CAS  Google Scholar 

  15. 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(6):193–197

    Article  CAS  Google Scholar 

  16. Lionetto L, Negro A, Palmisani S, Gentile G, Del Fiore MR, Mercieri M et al (2012) Emerging treatment for chronic migraine and refractory chronic migraine. Expert Opin Emerg Drugs 17(3):393–406

    Article  CAS  Google Scholar 

  17. Brighina F, Palermo A, Aloisio A, Francolini M, Giglia G, Fierro B (2006) Levetiracetam in the prophylaxis of migraine with aura: a 6-month open-label study. Clin Neuropharmacol 29(6):338–342

    Article  CAS  Google Scholar 

  18. Rapoport AM, Bigal ME (2005) Migraine preventive therapy: current and emerging treatment options. Neurol Sci : Off J Italian Neurol Soc Italian Soc Clin Neurophysiol 26(Suppl 2):s111–s120

    Article  Google Scholar 

  19. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ (Clinical Research ed) 339:–b2700

  20. 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? Control Clin Trials 17(1):1–12

    Article  CAS  Google Scholar 

  21. Sterne JA, Hernan MA, Reeves BC, Savovic J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ (Clinical research ed). 2016;355:i4919

  22. Schulz KF, Chalmers I, Hayes RJ, Altman DG (1995) Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Jama. 273(5):408–412

    Article  CAS  Google Scholar 

  23. Gallai V, Alberti A, Rossi C, Coppola F, Gallai B, Mazzotta G et al (2003) An open-label pilot study on the efficacy and tolerability of levetiracetam in the prophylaxis of migraine. J Headache Pain 4(2):92–96

    Article  Google Scholar 

  24. Rapoport AM, Sheftell FD, Tepper SJ, Bigal ME (2005) Levetiracetam in the preventive treatment of transformed migraine: A prospective, open-label, pilot study. Curr Therapeut Res Clin Experiment 66(3):212–221

    Article  CAS  Google Scholar 

  25. Brighina F, Cosentino G, Vigneri S, Talamanca S, Palermo A, Giglia G et al (2011) Abnormal facilitatory mechanisms in motor cortex of migraine with aura. Eur J Pain (London, England) 15(9):928–935

    Article  Google Scholar 

  26. Young W, Shaw J, Bloom M, Gebeline-Myers C (2008) Correlation of increase in phosphene threshold with reduction of migraine frequency: observation of levetiracetam-treated subjects. Headache. 48(10):1490–1498

    Article  Google Scholar 

  27. de Tommaso M, Guido M, Sardaro M, Serpino C, Vecchio E, De Stefano G et al (2008) Effects of topiramate and levetiracetam vs placebo on habituation of contingent negative variation in migraine patients. Neurosci Lett 442(2):81–85

    Article  Google Scholar 

  28. Kashipazha D, Ghadikolaei HS, Siavashi M (2017) Levetiracetam in Compare to Sodium Valproate for Prophylaxis in Chronic Migraine Headache: A Randomized Double-Blind Clinical Trial. Curr Clin Pharmacol 12(1):55–59

    Article  CAS  Google Scholar 

  29. FDA (2018) FDA approves novel preventive treatment for migraine

  30. Lattanzi S, Brigo F, Trinka E et al (2019) Erenumab for preventive treatment of migraine: a systematic review and meta-analysis of efficacy and safety. Drugs. 79(4):417–431

    Article  CAS  Google Scholar 

  31. Linde M, Mulleners WM, Chronicle EP, Mccrory DC (2013) Topiramate for the prophylaxis of episodic migraine in adults. The Cochrane database of systematic reviews. (6):Cd010610

  32. Linde M, Mulleners WM, Chronicle EP, McCrory DC 2013 Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. The Cochrane database of systematic reviews. (6):Cd010611

  33. Sadeghian H, Motiei-Langroudi R (2015) Comparison of Levetiracetam and sodium Valproate in migraine prophylaxis: A randomized placebo-controlled study. Ann Indian Acad Neurol 18(1):45–48

    PubMed  PubMed Central  Google Scholar 

  34. EMA. New measures to avoid valproate exposure in pregnancy endorsed. 2018

  35. He A, Song D, Zhang L, Li C (2017) Unveiling the relative efficacy, safety and tolerability of prophylactic medications for migraine: pairwise and network-meta analysis. J Headache Pain 18(1):26

    Article  Google Scholar 

  36. Ha H, Gonzalez A (2019) Migraine Headache Prophylaxis. Am Fam Physician 99(1):17–24

    PubMed  Google Scholar 

  37. Pakalnis A, Kring D, Meier L (2007) Levetiracetam prophylaxis in pediatric migraine—an open-label study. Headache. 47(3):427–430

    Article  Google Scholar 

  38. Miller GS (2004) Efficacy and Safety of Levetiracetam in Pediatric Migraine. Headache: J Head Face Pain 44(3):238–243

    Article  Google Scholar 

  39. Watkins AK, Gee ME, Brown JN (2018) Efficacy and safety of levetiracetam for migraine prophylaxis: A systematic review. J Clin Pharm Ther 43(4):467–475

    Article  CAS  Google Scholar 

  40. Awaad Y, Rizk T (2014) Levetiracetam in the treatment of pediatric headache. J Taibah Univ Med Sci 9(1):74–77

    Google Scholar 

  41. Meissner K, Fässler M, Rücker G et al (2013) Differential effectiveness of placebo treatments: A systematic review of migraine prophylaxis. JAMA Intern Med 173(21):1941–1951

    Article  Google Scholar 

  42. Jackson JL, Kuriyama A, Anton A, et al. (2019) The Accuracy of Google Translate for Abstracting Data From Non-English-Language Trials for Systematic Reviews. Ann Intern Med 30

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Clinic of Anesthesiology and Intensive Care, School of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece

    Georgia Tsaousi & Vasilios Grosomanidis

  2. Department of Clinical Pharmacology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, 54006, Thessaloniki, Greece

    Chryssa Pourzitaki, Spyridon Siafis, Athanassios Kyrgidis, Dimitrios Kouvelas & Georgios Papazisis

Authors
  1. Georgia Tsaousi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chryssa Pourzitaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Spyridon Siafis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Athanassios Kyrgidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Vasilios Grosomanidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Dimitrios Kouvelas
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Georgios Papazisis
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Chryssa Pourzitaki: Conception and design of the study, acquisition of data, analysis and interpretation of the data, drafted the manuscript, provided final approval of the revised version to be published, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Georgia Tsaousi: Conception and design of the study, analysis and interpretation of the data, drafted the manuscript, provided final approval of the revised version to be published.

Spyridon Siafis: Conception and design of the study, analysis and interpretation of the data, drafted the manuscript, provided final approval of the revised version to be published.

Georgios Papazisis: Conception and design of the study, analysis and interpretation of the data, drafted the manuscript, provided final approval of the revised version to be published.

Athanassios Kyrgidis: Conception and design of the study, analysis and interpretation of the data, drafted the manuscript, provided final approval of the revised version to be published.

Dimitrios Kouvelas: Conception and design of the study, analysis and interpretation of the data, drafted the manuscript, provided final approval of the revised version to be published.

Vasilios Grosomanidis: Conception and design of the study, analysis and interpretation of the data, drafted the manuscript, provided final approval of the revised version to be published.

Corresponding author

Correspondence to Chryssa Pourzitaki.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Appendix

Appendix

  1. 1.

    Search strategy, combining free text and Medical Subject Headings (MeSH terms), was set up for PubMed as follows:

    Search query: ((“migraine disorders”[MeSH Terms] OR (“migraine”[All Fields] AND “disorders”[All Fields]) OR “migraine disorders”[All Fields] OR “migraine”[All Fields]) OR (“headache”[MeSH Terms] OR “headache”[All Fields])) AND ((“etiracetam”[Supplementary Concept] OR “etiracetam”[All Fields] OR “levetiracetam”[All Fields]) OR (“etiracetam”[Supplementary Concept] OR “etiracetam”[All Fields] OR “keppra”[All Fields])) 126 hits

  2. 2.

    Search strategy, using combination of terms, was set up for Scopus as follows:

    Search query: TITLE-ABS-KEY ((levetiracetam OR keppra) AND (migraine OR headache)) 816 hits

  3. 3.

    Search strategy, using combination of terms, was set up for the Cochrane Central Register of Controlled Trials (CENTRAL) as follows:

    Search query: TITLE-ABS-KEY ((levetiracetam OR keppra) AND (migraine OR headache)) 74 hits

  4. 4.

    Search strategy, using combination of terms, was set up for the International Web of Science as follows:

    TOPIC: ((“levetiracetam” OR “keppra”) AND (migraine OR headache OR “migraine disorders”)) 207 hits.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tsaousi, G., Pourzitaki, C., Siafis, S. et al. Levetiracetam as preventive treatment in adults with migraine: an up-to-date systematic review and quantitative meta-analysis. Eur J Clin Pharmacol 76, 161–174 (2020). https://doi.org/10.1007/s00228-019-02790-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-019-02790-2

Keywords

Search

Navigation