Curr Treat Options Neurol (2019) 21: 16 DOI 10.1007/s11940-019-0558-1 Headache (JR Couch, Section Editor) Current Status of Antiepileptic Drugs as Preventive Migraine Therapy Simy K. Parikh, MD Stephen D. Silberstein, MD* Address *Jefferson Headache Center, Thomas Jefferson University, Suite 200, Philadel- phia, PA, 19107, USA Email: [email protected] Published online: 18 March 2019 * Springer Science+Business Media, LLC, part of Springer Nature 2019 This article is part of the Topical Collection on Headache Keywords Migraine I Headache I Preventive therapy I Pharmacology I Antiepileptic drugs I Anticonvulsants Abstract Background 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. Recent findings The potential role for new extended-release formulations of topiramate in migraine prevention is discussed. Summary 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 leveti- racetam, in migraine prevention and to clarify the role of gabapentinoids in headache management. 16 Page 2 of 15 Curr Treat Options Neurol (2019) 21: 16 Introduction Migraine is a neurologic disorder that causes signif- such as photophobia, phonophobia, nausea, or icant global disability and socioeconomic burden vomiting. Cortical spreading depression (CSD) is [1•, 2]. It is associated with substantial healthcare thought to be integral in the pathophysiology of costs, reduced work productivity, and social limita- migraine. CSD is a wave of brief neuronal excitation tions [3–5]. Patients with a chronic or disabling followed by neuronal inhibition that propagates migraine are offered pharmacological preventive op- slowly across the cortex [8•, 9]. In its wake, CSD tions to reduce the frequency of migraine exacerba- results in the extracellular release of potassium ions, tions and improve the efficacy of medications used hydrogen ions, and glutamate, which activate men- to stop exacerbations [1•, 6••]. However, less than ingeal nociceptors. This induces an antidromic axo- half of the patients choose to use preventive therapy nal reflex that causes sensory trigeminovascular [1•, 7].Factorssuchaspoormedicationefficacyand axons innervating the pia and dura to release vaso- tolerability and incomplete understanding of avail- active neuropeptides such as substance P and calci- able options and benefits play a role in inadequate tonin gene-related peptide (CGRP), leading to neu- use of preventative therapy [7]. This review on the rogenic inflammation [8•, 10]. With repeated or use of antiepileptic drugs (AEDs) for migraine- continued activation, trigeminovascular neurons preventive treatment in adults discusses the most eventually develop sensitization, or an amplified re- widely used preventive AEDs, topiramate and sponsiveness and a reduced response threshold to divalproex sodium/sodium valproate. We also dis- stimuli [8•]. The general role of AEDs in migraine cuss zonisamide and levetiracetam, AEDs that may prevention lies in their potential to block CSD and be on the horizon of migraine-preventive care, and prevent central sensitization [9, 11]. Generally, AEDs comment on gabapentin, pregabalin, carbamaze- act by stabilizing neuronal membranes through their pine, oxcarbazepine, and lamotrigine, which have effect on voltage and receptor-gated ion channels insufficient evidence for use in migraine prevention. and reducing the release of vasoactive neuropeptides It is important to understand the efficacy and toler- [9]. ability of each agent in selecting migraine-preventive Topiramate and divalproex sodium/sodium therapy (see Fig. 1). valproate are the only two FDA-approved AEDs for migraine prevention and are substantiated by high-quality evidence. A 2013 Cochrane review did Mechanisms of AEDs in migraine prevention not show a benefit toward reduced headache fre- Migraine is a neurological disorder characterized by re- quency from carisbamate, clonazepam, lamotrigine, curring attacks of head pain, accompanied by symptoms oxcarbazepine, pregabalin, or vigabatrin [12•, 13]. Fig. 1. Comparative efficacy vs. tolerability of select AEDs used in migraine prevention. Curr Treat Options Neurol (2019) 21: 16 Page 3 of 15 16 While the review also did not show a benefit in these medications may still have a role in migraine using zonisamide, levetiracetam, and gabapentin, prevention. FDA-approved AEDs for migraine prevention Topiramate History Topiramate (TPM) (Topamax®) was first synthesized in 1979 as an inter- mediate product in a study of fructose-1,6-diphosphate and its inhibition of gluconeogenesis to treat diabetes [14, 15•, 16••]. Researchers noticed that while TPM did not have a hypoglycemic effect, it has a structural resemblance to carbonic anhydrase inhibitors, which propelled its seren- dipitous discovery as an anticonvulsant and eventually as a preventive treatment for migraine [14]. Chemically, TPM is derived from the natu- rally occurring monosaccharide D-fructose and has a weakly acidic sulfamate group [14]. It readily enters the central nervous system (CNS) [14]. It is unique in those oxygen atoms, which contribute to hydrogen bond formation, account for nearly 40% of its mass [14, 15•]. Mechanism of action TPM has variable activity on four protein complexes that are regulated by protein kinase phosphorylation: voltage-gated sodium channels, high- voltage-gated calcium channels, GABAA receptors, and AMPA/kainate re- ceptors [14, 16••]. TPM’s variable activity is likely due to its need to attach to protein complexes in the dephosphorylated state [14]. In the dephosphorylated state, TPM’s unique structure, with its high number of oxygen atoms, allows it to form hydrogen bonds with protein complexes [14]. On binding, TPM then has a positive or negative allosteric modu- latory effect on the channels [14, 17]. Furthermore, bound TPM prevents further phosphorylation of these channels, allowing it to have an in- creased, albeit delayed, modulatory effect over time [14]. Unlike other AEDs used in migraine prevention, TPM negatively mod- ulates AMPA/kainate receptors, which indirectly inhibits the activity of the N-methyl-D-aspartic acid (NMDA) receptor, a glutamate receptor found on nerve cells [15•, 16••]. Glutamate is neuro-excitatory and is a majorneurotransmitterinvolvedinCSD[18]. Therefore, this inhibitory action of TPM is its most significant in both its anticonvulsant and anti- migraine properties [15•, 16••]. TPM also negatively modulates voltage-gated sodium channels and high-voltage-gated calcium channels, although the extentoftheseroles in TPM’s overall clinical pharmacology is not yet clear [15•]. Negative modulation of voltage-gated sodium channels prevents the propagation of the action potential. This in turn stabilizes neuronal membranes, which leads to a decrease in neuropeptide release and decreased neuronal hyperexcitability [9, 14, 15•, 16••]. Negative modulation of high-voltage- gated calcium channels prevents sustained membrane depolarization, 16 Page 4 of 15 Curr Treat Options Neurol (2019) 21: 16 leading to increased membrane stability [9, 14, 15•, 16••, 19]. It also reduces the release of neuropeptides and neurotransmitters, such as CGRP and glutamate from trigeminovascular nerve terminals [20, 21]. The relationship of TPM with GABAA receptors is complex [15•, 22]. GABA is an inhibitory neurotransmitter distributed widely in the CNS. GABAA receptors in pyramidal neurons of the hippocampus mediate normal inhibitory postsynaptic potentials as well as depolarizing poten- tials. It is thought that TPM, by preventing protein phosphorylation, causes a shift in the equilibrium potential and partially inhibits depolarizing potentials [15•]. TPM also selectively but not specifically inhibits isoenzymes II and IV of carbonic anhydrase [15•]. While the relevance of carbonic anhydrase inhibition in migraine prevention is not known, it can lead to decreased neuronal excita- tion and increase inhibitory responses [14, 16••]. TPM’s role in carbonic anhydrase inhibition may also lead to its ability to activate a hyperpolarizing potassium conductance [23]. By targeting multiple protein complexes, TPM has been shown to inhibit CSD [16••, 24–27]. This multimodal impact is also likely the reason TPM is more efficacious than other AEDs [16••]. Efficacy The efficacy of TPM in treating both episodic and chronic migraine has been widely studied [6••, 16••, 28, 29••, 30–36, 37••, 38••, 39–41]. TPM, given in doses ranging from 100 to 200 mg/day, is effective in migraine prevention, although studies have suggested that doses of 200 mg/day are no