Current Status of Antiepileptic Drugs as Preventive Migraine Therapy
Antiepileptic drugs (AEDs) are an important class of agents used in the treatment of migraine, a neurological disorder that imparts significant socioeconomic burden. It is important for neurologists to understand the rationale for AEDs in migraine-preventive treatment, as well as each agent’s efficacy and tolerability profile, in order to best determine clinical care.
Purpose of this review
This article specifically provides the following: (1) a review of the mechanism of action, efficacy, and tolerability of topiramate and divalproex sodium/sodium valproate, the most widely used AEDs for migraine prevention, (2) a discussion on emerging evidence regarding the efficacy of zonisamide and levetiracetam, and (3) comments on gabapentin, pregabalin, carbamazepine, oxcarbazepine, and lamotrigine, AEDs which have insufficient evidence for use in migraine prevention.
The potential role for new extended-release formulations of topiramate in migraine prevention is discussed.
There is substantial evidence supporting the use of AEDs in migraine prevention. Specific agents should be chosen based on their efficacy and tolerability profiles. Further studies are needed to determine the efficacy of the newer AEDs, zonisamide and levetiracetam, in migraine prevention and to clarify the role of gabapentinoids in headache management.
KeywordsMigraine Headache Preventive therapy Pharmacology Antiepileptic drugs Anticonvulsants
The research was partially funded by The Groten Family Fund.
Compliance with Ethical Standards
Conflict of Interest
Stephen D. Silberstein reports personal fees from Alder Biopharmaceuticals, grants and personal fees from Allergan, grants and personal fees from Amgen, grants and personal fees from Avanir Pharmaceuticals Inc., personal fees from eNeura, non-financial support from Curelator, Inc., grants and personal fees from electroCore Medical, LLC, grants and personal fees from Dr. Reddy’s Laboratories, personal fees from Medscape, LLC, grants and personal fees from Teva Pharmaceuticals, grants and personal fees from Supernus Pharmaceuticals, Inc., grants and personal fees from Eli Lilly and Company, personal fees from Theranica, non-financial support from Trigemina, Inc., outside the submitted work. Simy Parikh declares that she has no conflicts of interest.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.• Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68:343–9 This article highlights the significant socioeconomic burden of migraine and the need for efficacious preventive therapy.Google Scholar
- 2.Vos T, Barber RM, Bell B, Bertozzi-Villa A, Biryukov S, Bolliger I, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;386:743–800.Google Scholar
- 3.Stokes M, Becker WJ, Lipton RB, Sullivan SD, Wilcox TK, Wells L, et al. Cost of health care among patients with chronic and episodic migraine in Canada and the USA: results from the International Burden of Migraine Study (IBMS). Headache. 2011;51(7):1058–77.Google Scholar
- 5.Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States data from the American migraine study II. Headache. 2001;41:646–57.Google Scholar
- 6.•• Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: Table 1. Neurology. 2012;78:1337–45 This article provides updated evidence-based recommendations based for AEDs in the preventive treatment of migraine headache.PubMedPubMedCentralGoogle Scholar
- 7.Minen MT, Anglin C, Boubour A, Squires A, Herrmann L. Meta-synthesis on migraine management. Headache J Head Face Pain. 2018;58:22–44.Google Scholar
- 12.•• Linde M, Mulleners WM, Chronicle EP, McCrory DC. Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013;(6):CD010608 This is a comprehensive assessment from controlled trials on the efficacy and tolerability of AEDs in migraine-preventive therapy.Google Scholar
- 13.•• Linde M, Mulleners WM, Chronicle EP, McCrory DC. Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013:1–50 This is a comprehensive assessment from controlled tmigraine-preventive therapy.Google Scholar
- 15.• Shank RP, Maryanoff BE. Molecular pharmacodynamics, clinical therapeutics, and pharmacokinetics of topiramate. CNS Neurosci Ther. 2008;14:120–42 This is a comprehensive review of the molecular and pharmacological aspects of topiramate.Google Scholar
- 16.•• Silberstein SD. Topiramate in migraine prevention: a 2016 perspective. Headache J Head Face Pain. 2017;57:165–78 This article provides an updated, comprehensive review on the molecular targets, efficacy, and tolerability of topiramate.Google Scholar
- 27.Ayata C, Jin H, Kudo C, Dalkara T, Moskowitz MA. Suppression of cortical spreading depression in migraine prophylaxis. Ann Neurol. 2006;59:652–61.Google Scholar
- 29.•• Silberstein S, Lipton R, Dodick D, Freitag F, Mathew N, Brandes J, et al. Topiramate treatment of chronic migraine: a randomized, placebo-controlled trial of quality of life and other efficacy measures. Headache. 2009;49:1153–62 This study provides data on the benefit of topiramate on clinically relevant secondary outcomes in migraine prevention.Google Scholar
- 30.Diener H-C, Bussone G, Van Oene JC, Lahaye M, Schwalen S, Goadsby PJ, et al. Topiramate reduces headache days in chronic migraine: a randomized, double-blind, placebo-controlled study. Cephalalgia. 2007;27:814–23.Google Scholar
- 34.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.Google Scholar
- 38.•• Silberstein SD, Neto W, Schmitt J, Jacobs D. MIGR-001 Study Group. Topiramate in migraine prevention. Arch Neurol. 2004;61:490 This is a double-blinded, placebo-controlled study providing data on the efficacy and safety of topiramate as a migraine-preventive therapy.Google Scholar
- 39.Storey JR, Calder CS, Hart DE, Potter DL. Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache. 41(10):968–75.Google Scholar
- 51.Löscher W. The discovery of valproate. In: Löscher W, editor. Valproate Milestones in Drug Therapy. Birkhäuser, Basel; 1999.Google Scholar
- 52.•• Silberstein SD. Divalproex sodium in headache: literature review and clinical guidelines. Headache J Head Face Pain. 1996;36:547–55 This is a comprehensive review on the molecular targets and efficacy of divalproex sodium for migraine prevention.Google Scholar
- 54.Hering R, Kuritzky A. Sodium valproate in the prophylactic treatment of migraine: a double-blind study versus placebo. Cephalalgia. SAGE PublicationsSage UK: London, England. 1992;12:81–4.Google Scholar
- 55.Jensen R, Brinck T, Olesen J, Goldstein J, Saper J, Silberstein S, et al. Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology. 1994;44:647–51.Google Scholar
- 60.•• Linde M, Mulleners WM, Chronicle EP, McCrory DC. Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013;(6):CD010611 This is a comprehensive assessment from controlled trials on the efficacy and tolerability of valporate in migraine-preventive therapy.Google Scholar
- 61.•• Silberstein SD, Collins SD. Safety of divalproex sodium in migraine prophylaxis: an open-label, long-term study. Long-term safety of Depakote in headache prophylaxis study group. Headache. 1999;39:633–43 This is an open-label study providing evidence for the long-term safety of divalproex sodium for migraine prevention.Google Scholar
- 66.Villani V, Ciuffoli A, Prosperini L, Sette G. Zonisamide for migraine prophylaxis in topiramate-intolerant patients: an observational study. Headache J Head Face Pain. 2011;51:287–91.Google Scholar
- 81.•• Silberstein S, Goode-Sellers S, Twomey C, Saiers J, Ascher J. Randomized, double-blind, placebo-controlled, phase II trial of gabapentin enacarbil for migraine prophylaxis. Cephalalgia. 2013;33:101–11 This is a double-blinded, placebo-controlled study providing evidence that gabapentin does not significantly differ from placebo when used for migraine-preventive therapy.Google Scholar
- 89.•• Silberstein S, Saper J, Berenson F, Somogyi M, McCague K, D’Souza J. Oxcarbazepine in migraine headache: a double-blind, randomized, placebo-controlled study. Neurology. 2008;70:548–55 This is a double-blinded, placebo-controlled study providing evidence that oxcarbazepine does not significantly differ from placebo when used for migraine-preventive therapy.PubMedGoogle Scholar
- 93.Veroniki AA, Cogo E, Rios P, Straus SE, Finkelstein Y, Kealey R, et al. Comparative safety of anti-epileptic drugs during pregnancy: a systematic review and network meta-analysis of congenital malformations and prenatal outcomes. BMC Med. BioMed Central. 2017;15:95.Google Scholar