Topiramate in Migraine Prevention: A 2016 Perspective.

Background In evidence-based guidelines published in 2000, topiramate was a third-tier migraine preventive with no scientific evidence of efficacy; recommendation for its use reflected consensus opinion and clinical experience. Its neurostabilizing activity, coupled with its favorable weight profile, made topiramate an attractive alternative to other migraine preventives that caused weight gain. When guidelines for migraine prevention in episodic migraine were published in 2012, topiramate was included as a first-line option based on double-blind, randomized controlled trials involving nearly 3000 patients. The scientific and clinical interest in topiramate has generated a large body of data from randomized controlled trials, meta-analyses, patient registries, cohort studies, and claims data analyses that have more fully characterized its role as a migraine preventive. Aim This article will review the profile of topiramate that has emerged out of the past decade of research and clinical use in migraine prophylaxis. It will also address the rationale for extended-release (XR) formulations in optimizing topiramate therapy in migraine. Summary Topiramate has activity at multiple molecular targets, which may account for why it is effective in migraine and most other, more specific, anticonvulsants are not. Based on randomized controlled trials, topiramate reduces migraine frequency and acute medication use, improves quality of life, and reduces disability in patients with episodic migraine and in those with chronic migraine with or without medication overuse headache. Its efficacy in chronic migraine is not improved by the addition of propranolol. Topiramate's ability to prevent progression from high-frequency episodic migraine to chronic migraine remains unclear. Consistent with clinicians’ perceptions, migraineurs are more sensitive to topiramate-associated side effects than patients with epilepsy. Paresthesia is a common occurrence early in treatment but is rarely cause for terminating topiramate treatment. Cognitive problems occur much less frequently than paresthesia but are more troublesome in terms of treatment discontinuation. Cognitive complaints can often be managed by slowly increasing the topiramate dose in small increments to allow habituation. As with other carbonic anhydrase inhibitors, topiramate has metabolic effects that favor the development of metabolic acidosis and possibly renal stones. Because migraineurs have an increased risk of renal stones independent of topiramate exposure, clinicians should counsel all migraine patients to maintain hydration. Abrupt onset of blurring, other visual disturbances, and/or ocular pain following topiramate's initiation should be evaluated promptly since this may indicate rare but potentially sight-threatening idiosyncratic events. Postmarketing evidence has shown that first-trimester exposure to topiramate monotherapy is associated with increased occurrence of cleft lip with or without cleft palate (Pregnancy Category D). Even though topiramate's long half-life would seemingly support q.d. dosing, randomized controlled migraine trials used b.i.d. administration of immediate-release (IR) topiramate, which has more favorable plasma concentration-time profile (ie, lower peak concentrations and higher trough concentrations) than q.d. IR dosing. Given the sensitivity of migraineurs to topiramate-related adverse events, particularly cognitive effects, pharmacokinetic profiles should be considered when optimizing migraine outcomes. The extended-release (XR) formulations Qudexy® XR (Upsher-Smith Laboratories) and Trokendi XR® (Supernus Pharmaceuticals) were specifically designed to achieve the adherence benefits of q.d. dosing but with more favorable (ie, more constant) steady-state plasma concentrations over the 24-hour dosing interval vs IR topiramate b.i.d. Intriguing results from a study in healthy volunteers showed consistently less impairment in neuropsychometric tests of verbal fluency and mental processing speed with an XR topiramate formulation (Trokendi XR) vs IR topiramate b.i.d. These findings suggest a pharmacodynamic effect associated with significantly reducing plasma concentration fluctuation when topiramate absorption is slowed. Results of retrospective studies in migraineurs treated with XR topiramate appear to support a clinically meaningful benefit of XR topiramate vs IR topiramate in terms of significantly fewer cognitive effects, improved adherence, and overall better outcomes of migraine prophylaxis with topiramate.