Migraine Myth of the Month: Prescription Labels
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Read the labels on your migraine prescriptions carefully – they always are based on meticulously derived scientific research (Myth!)
Years ago I wrote an editorial entitled “Margaritas… Not Science” which described a major initial step taken in the development of injectable sumatriptan, the drug that launched a therapeutic revolution in migraine that is still ongoing. Put simply, a handful of colleagues and I had assembled at a coastal southeast Florida resort to refine what would become the protocol for the first wide-scale clinical research study involving sumatriptan conducted in the United States. It was a beautiful Florida night, and to catalyze the process we ordered a picture or two of tasty margaritas.
At that time we had only an incomplete idea as to the biologic process that generated migraine and a similarly incomplete knowledge of how sumatriptan might work to terminate an acute migraine headache. Assuming that the major mechanism of action of the drug involved constricting cranial blood vessels, we took pains to exclude from the study any potential participant who might be at particular risk for a vascular complication such as heart attack or stroke. In particular, our exclusion criteria included individuals over the age of 65 or those of any age with a history of stroke or clinically evident coronary artery disease (CAD).
That was almost 40 years ago, and in the time that has passed we have come to learn that (a) the biology of migraine is complex and involves far more than simply constriction of cranial blood vessels, and (b) for sumatriptan – and all of the triptans – the primary mechanism of action in halting migraine likely involves stimulation of receptors within migraine’s biologic circuitry that block the transmission of head pain signal. Both when we conceived the initial study’s protocol and over the 34 years since the drug was approved for use in the US, there has emerged no clear evidence that sumatriptan is any more likely to cause a significant vascular side effect in patients over 65 or those who have a history of stroke or clinically evident CAD than in younger patients or patients lacking a history of stroke, heart attack or other clinical manifestations of CAD. If one reviews the published medical literature, those few cases of stroke or heart attack that have occurred in temporal association with use of a triptan typically have involved individuals lacking risk factors for those vascular events. And yet the label remains the label, and that label more or less mirrors the protocol from a study performed when our knowledge of migraine biology and triptan mechanism of action was far from complete.
Moreover, the current label for injectable sumatriptan includes an admonition to avoid use of injectable sumatriptan if another triptan has been used within the previous 24 hours. As this issue’s “Tip of the Month” outlines, we encourage patients to match their acute therapy to the present intensity of their migraine headache and specifically to use injectable sumatriptan as “rescue” therapy if headache intensity has escalated despite earlier use of an oral triptan. In contrast to the label for injectable sumatriptan, this recommendation is derived from a clinical trial published in the peer-reviewed medical literature in 2011 (“Mixing Triptans“: Patient Satisfaction.Headache 2011; 51: 135).
Rimegepant (Nurtec) is an FDA-approved and frequently prescribed medication for both acute migraine treatment and for migraine prevention. As the label indicates, the approved and recommended dose for acute migraine treatment is one per day, and the dose for migraine prevention is one tablet every other day. Why? Because a second dose taken within the same day for acute migraine is ineffective or might be dangerous? Because Nurtec taken every other day for migraine prevention similarly might be dangerous? No. There is no scientific evidence to support this, but it was how the protocols for the Nurtec studies were designed. Why were they designed that way? Good question, and don’t be surprised if Nurtec’s owner undertakes research to permit eventual relabeling for a second dose for acute migraine and for daily dosing for migraine prevention.
The art and science involved in the conduct of clinical research are inevitably imperfect, and this definitely extends to protocol development. Often during the course of a an extended clinical research trial it becomes obvious that the inclusion/exclusion criteria, outcomes chosen for primary evaluation or other key components were inappropriate. New knowledge emerges either from the clinical trial itself or elsewhere, and that knowledge may invalidate portions of the protocol.
Sometimes the study protocol can be revised mid-stream to reflect this new knowledge. When we conducted the first large-scale American study of tissue plasma activator (t-PA) for the treatment of acute stroke, the primary clinical endpoint chosen for evaluation was clinical status at 24 hours following treatment. An interim analysis demonstrated that in the acute stroke patients studied there was no clear difference in the clinical status of patients receiving t-PA versus placebo at 24 hours but a clear separation between the groups at 3 months. The NIH permitted the investigators to change the primary endpoint to clinical status at 3 months, and by the early 2000s intravenous t-PA had become the standard of care for acute stroke.
But t-PA was an exception. Many times we find that new drugs may be safe, well-tolerated and effective even when the studies used to evaluate those drugs are conducted with protocols that contain flaws. Because with new drugs the protocols utilized in phase 3 studies typically become the labels once the drugs are made available for general clinical use, the labels may be inaccurate. And – once adopted – drug labels are often difficult to change.
How can you as a patient determine whether or not the details of a given drug’s label are accurate and relevant to your situation? Not an easy question to answer, but no answer will be forthcoming unless you ask. If your provider or others you ask are uncertain, ask a headache medicine sub-specialist or an informed third-party source such as the American Headache Society (AHS), National Headache Foundation (NHF) or this magazine (edoffice@migraineurmagazine.com). While none of the latter sources can provide specific clinical advice, all can address more general questions pertaining to a given medication.
JFR
