Migraine Treatments of the Month: Topiramate
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Examined through the lens of the historical development of therapies for migraine, topiramate is a particularly interesting drug. Like virtually all medications prescribed for migraine prior to the advent of sumatriptan in the early 1990s, topiramate was first intended as a treatment for another medical disorder (in its case, epilepsy) and subsequently – some would say serendipitously – found to be effective for migraine. Topiramate bridges the gap between old-timers for migraine prevention such as amitriptyline (Elavil) and propranolol (Inderal) that were developed for the treatment of depression and high blood pressure, respectively, and then found to be useful for migraine and “designer drugs” such as the anti-CGRP monoclonal antibodies and the “gepants” that were developed specifically for migraine.
In what sense was topiramate a “bridge” therapy? The emergence of topiramate as a potential therapy for migraine prevention coincided with a new understanding that migraine is a disorder characterized by brain “hypersensitivity” and that medications which suppress that hypersensitivity can reduce migraine burden as well as, say, prevent seizures. Or stabilize bipolar disorder. Or inhibit compulsive behavior.
The topiramate “immediate release” (IR) formulation (initially marketed as Topamax) received FDA approval for the treatment of epilepsy in 1996, and eventually enough research data accumulated to support the FDA extending the drug’s indication to include migraine prevention. From the outset it was clear to all of us engaged in the clinical development of topiramate for migraine that this medication represented a major step forward in migraine therapeutics. Also clear from the outset was that the drug would be difficult for many migraineurs to tolerate.
Almost 20 years have passed since topiramate received its FDA approval for use in migraine prevention, and during those years such therapies as onabotulinumtoxinA (BotoxA) and, more recently, the anti-CGRP drugs have emerged as attractive alternatives. Unlike many of the older medications that never have been compared to the newer kids on the block for their safety, tolerability and effectiveness, topiramate is practically unique in the amount of effort that has gone into evaluating its effectiveness relative to its competitors.
The multicenter FORWARD study examined topiramate versus BotoxA for their clinical utility in treating chronic migraine. While the two therapies were more or less equally effective in treating chronic migraine for those research subjects who completed the treatment phase, a much higher percentage of patients randomized to topiramate found the drug difficult or impossible to tolerate; the discontinuation rate in that group was far greater than it was in the group randomized to receive BotoxA. In a subsequent study again involving patients with chronic migraine, erenumab (Aimovig) was similarly much easier than topiramate for the research patients to tolerate, and the effectiveness of Aimovig in reducing migraine burden was significantly higher.
Even starting with a low-dose and sequentially increasing to a target therapeutic dose of 50 mg twice daily, topiramate produces a strange intermittent “tingling” over various parts of the body in as many as 1/3rd of patients. While this side effect is benign and typically transient, of more concern are the potential side effects of impaired concentration, impaired memory and word-finding difficulties/decreased verbal fluency. The extended release/administered once-daily formulation of topiramate is less likely to produce cognitive side effects, but it is typically difficult to prescribe consequent to its higher cost and the corresponding disinclination of insurers to authorize its use.
So why does topiramate IR remain near or even at the top of prevention therapies for migraine prescribed by medical providers? The most obvious answer: the drug is generic and consequently far cheaper than either BotoxA or the new “designer drugs” such as the anti-CGRP monoclonal antibodies and the gepants. In the interest of protecting the financial bottom line, insurers consequently prefer that providers prescribe topiramate IR and often require that a patient try and fail the drug before something more tolerable and at least as effective may be prescribed. There is really no other compelling reason for a provider to prescribe topiramate for migraine prevention.
This “dance with the devil” involving providers and insurers has been described elsewhere in this magazine, but suffice it to say that for virtually all migraineurs whose migraine burdens are such that a course of prevention therapy is required, there are better alternatives than topiramate.
