Migraine Treatments of the Month: The Oral Triptans
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In this issue’s “Migraine Treatment of the Month” and in an effort which is long overdue, we turn our attention to the oral triptans.
This class of medications has played a critical role in the history of how migraine therapeutics has evolved over the past three decades. While in recent years a great deal of attention rightfully has been directed towards the anti-CGRP medications and the new therapeutic options they represent, both within the US and internationally the oral triptans continue to occupy an important place in our current arsenal of weapons for treating acute migraine.
It is in part because of their historical and therapeutic importance that we have devoted more content than usual to this “Treatment of the Month” section, but we did so also because the triptans provide insight into the greater issue of how drug development “works” in our country. The purpose here is neither to glorify nor vilify our current system of drug development or the pharmaceutical industry itself, but rather to help our readers understand how new therapies travel the spectrum from their beginnings as an abstract concept through the painstaking process of “bench to bedside” research to the final endpoint of widespread clinical availability and use.
Is that process flawed? Yes. Has it produced near-miraculous new treatments that have yielded an improved quality of life? Definitely. Can we do better? We can, and we will.
The Oral Triptans
One can argue that for the United States the ongoing revolution in migraine therapeutics began with the introduction of injectable sumatriptan (Imitrex) in 1992. While dihydroergotamine (DHE) can make a legitimate claim to having been the first “designer drug” for migraine (ie, a therapy specifically developed for migraine treatment and not naturally occurring in the environment nor synthesized for another medical purpose and subsequently found to be effective for migraine as well), it was injectable sumatriptan that really got the therapeutic ball rolling for migraine.
Even after three decades plus, injectable sumatriptan remains the most effective self-administered therapy for rescue from moderate to severe migraine headache. It is for many millions of migraineurs literally “an ER in my pocket”, empowering them to safely, effectively, and efficiently subdue migraine episodes that otherwise would compel them to suffer in silent misery at home or seek urgent/emergent medical attention. Ironically, analysis of studies examining therapies administered for acute migraine headache in the ER place injectable sumatriptan at or near the top of the list – a list otherwise comprised of medications requiring intravenous or intramuscular administration - in terms of effectiveness. Despite this, injectable sumatriptan remains woefully under-prescribed.
Why? Why should such an effective therapy not be employed more frequently to assist in reducing the enormous public health burden imposed by migraine? Why should we continue to spend thousands of dollars managing a migraine patient who presents to an ER for an acute headache when a self-administered generic medication could have circumvented the ER visit altogether?
Part of the answer lies in the persistent misperception that the triptans are potentially quite unsafe, and no small part of that misperception in perpetuated by healthcare providers. Contributing to and dovetailing with that misperception is the tendency for the triptans to produce side effects such as chest pressure or neck “squeezing” that typically are benign and transient but understandably may be considered by the uninformed to indicate impending heart attack or an anaphylactic reaction. While the the familiar array of triptan side effects may occur with any triptan or triptan formulation (oral, injectable, inhaled) and tend to be more prominent if administration is delayed until the migraine attack has become more advanced, the side effects are most common and more prominent with injectable sumatriptan.
Why? To answer that requires a quick digression to considering a few important aspects of “pharmacokinetics”… a term which relates to how a given drug is handled by the body.
Two particularly relevant aspects of pharmacokinetics as related to the triptans are “Tmax” and “C max”. Tmax refers to the amount of time required for a drug to reach its maximal concentration in the blood following its administration. Cmax refers to the highest blood concentration achieved by that drug.
Consequent to its subcutaneous administration, injectable sumatriptan has the Tmax of a rocket-ship. In contrast, the Tmax of an orally administered triptan has the Tmax of your neighbor’s Prius. Along with this, the rocket-ship delivery of injectable sumatriptan is matched by a much higher Cmax than is achieved by the oral triptans. Combine these two factors, and you have a much higher drug level achieved much more rapidly. Upside for injectable sumatriptan: higher likelihood of headache relief + faster relief. Downside: higher likelihood of side effects
Like an especially prolific hen stimulated to drop egg after egg, the advent of injectable sumatriptan rapidly led the pharmaceutical industry to develop a succession of oral triptans that would possess a mechanism of action similar to injectable sumatriptan but, obviously, require no needle and also produce less frequent and less prominent side effects.
Thus we currently have available in the US 5 “fast onset” oral triptans: sumatriptan, zolmitriptan (Zomig), rizatriptan (Maxalt), almotriptan (Axert) and eletriptan (Relpax); 2 “slow onset” oral triptans: naratriptan (Amerge), and frovatriptan (Frova); and a compound tablet containing a combination of a more rapidly absorbed formulation of oral sumatriptan, and, with it, naproxen sodium (initially marketed as Treximet).
Which may lead one to question…
Are these oral triptans effective?
Yes. In well-designed and well conducted clinical trials involving patients with acute migraine of moderate to severe intensity, each was more effective than placebo in terms of statistical significance.Are any as effective as injectable sumatriptan for the treatment of acute migraine of moderate to severe intensity?
No. And hardly surprising, given injectable sumatriptan’s much faster Tmax and higher Cmax…not to mention its ability to exert a therapeutic effect even in the presence of migraine-associated nausea and vomiting, gastroparesis (ie, delayed stomach emptying) or both.Are side effects less frequent and less prominent with the oral triptans than with injectable sumatriptan?
Yes. Again, the faster, T-max and higher C max of injectable sumatriptan carries with the advantage of greater therapeutic effectiveness but also the burden of more frequent and prominent side effects.Are the oral triptans more effective when given early, when the migraine headache is of mild to moderate intensity rather than moderate to severe?
Yes. For a variety of reasons, the effectiveness of all the oral triptans - and, for that matter, probably all other classes of oral agents used to treat acute migraine headache - will be greater when they are administered early rather than late.If injectable sumatriptan is more effective than the oral triptans for moderate to severe acute migraine and the oral triptans are more likely to work if taken early, shouldn’t injectable sumatriptan also be administered earlier in the migraine episode…even at the onset of headache?
No. When a migraine headache has become moderate to severe in intensity, speed (i.e., Tmax) matters. When the migraine headache is beginning to develop and the pain is still at the level of mild to moderate, speed is less important; orally administered medication – including oral triptans –may be quite effective at that point. As effective as injectable sumatriptan? Unclear, but there is some limited evidence to suggest that administration of injectable sumatriptan too early in a migraine episode may be less likely to be effective than administration when the headache is more severe… the converse of what occurs with the oral triptans.What is the advantage of the “slow-onset” triptans?
These triptans (naratriptan and frovatriptan) have a slower Tmax and longer “half-lives”* than their fast-onset molecular cousins (*half-life=the time taken for ½ of the a given drug to be cleared from the body; generally it takes about 4 half-lives for a drug to be cleared entirely). Although it’s possible to take make too much of Tmax, Cmax and half-life when it comes to clinical relevance, it does appear that with their longer Tmax times naratriptan and frovatriptan are somewhat less likely to be effective in relieving headache than the fast-onset triptans within the first 2 hours following administration. They also are less likely to cause the typical triptan side effects, and with their longer half-lives (4-6 hours for naratriptan and 26 hours for frovatriptan), the 2 slower-onset but longer-present triptans may be associated with a lower likelihood of early recurrence of headache than their fast-onset brethren.
All this said, there are unquestionably many individual migraineurs who find that a fast-onset oral triptan will consistently relieve their moderate to severe headaches and will do so just as well as injectable sumatriptan and with less frequent/less prominent side effects. Other migraineurs will report that their moderate to severe headaches respond quite well and rapidly to either of the 2 “slow-onset” options. Not to overbeat this paradoxical drum, but this all goes to underscore yet again that the only “always” about migraine is that nothing is ever “always”.
Some additional clinical pearls
A decent amount of evidence exists to indicate that combining an oral nonsteroidal anti-inflammatory drug (NSAID) with an oral triptan is more effective than an oral triptan alone (the NSAIDs with the strongest evidence base in this regard are naproxen sodium and ibuprofen).
All of the fast-onset oral triptans have relatively short half-lives in the body, and injectable sumatriptan has a particularly short half-life (it is essentially gone from the body within a few hours). When migraine patients report that a triptan is causing “rebound” headache, with the implication that the drug is producing a second and often more severe headache, what most often they actually are experiencing is this: administration of the triptan significantly reduces or even eliminates the headache, but the biologic circuitry generating the headache has remained active and simply reignites when the triptan has passed from the body. Anticipate this, and especially so if the triptan you administered has not entirely eliminated the initial headache. Be ready for the headache to reemerge and treat it appropriately when it does.
There is no “best” oral triptan. Head-to-head comparator trials are few, and extensive clinical experience clearly indicates that often for a given patient “not all triptans are created equal”. Failure to respond to one oral triptan does not reliably predict failure to respond to another. On the other hand, if you have tried 3 oral triptans and have had no luck, it may be that your particular migraine circuitry is such that the triptan mechanism of action is not suited to your needs. Time to switch to another class of medications. The same can be said of those who do not find that the triptans provide headache relief but that the price paid in terms of side effects is too high. Time to try another class.
Clinicians often hear from migraine patients that a given oral triptan which was reliably effective for months or even years now is letting them down. The biomolecular basis for the development of this apparent triptan “tolerance” is unknown, but it occurs far too commonly to be dismissed as hearsay. In such situations simply switching to another triptan may be effective. If not, time to try a new class of medication.
Editor’s note
The pharmaceutical companies are not dumb, and contrary to what many would have you believe, they are not inherently malevolent. The scientists and physician scientists who work for those companies typically are bright and talented individuals. While there are unquestionably a few bad apples – and some very few (thankfully) very bad apples, amongst the vast orchard – most are dedicated to raising the standard of medical care and thus improving quality of life for their fellow citizens.
The pharmaceutical companies who employ them share that dedication. They also are businesses operating in a capitalist economy, and they consequently are dedicated to making a profit. They’d better be, or they will crumble into dust to be blown away by the winds of competition.
It became clear very quickly to the pharmaceutical industry that injectable sumatriptan’s emergence held tremendous implications for drug development in the area of migraine, a disorder, afflicting many millions of Americans. Think of it: upwards of 40 million potential patients/customers…a HUGE market. What medical market could be larger? Obesity? Insomnia? Alzheimer’s? Maybe. But in the early ‘90s, break-thru therapies for obesity and insomnia had yet to emerge (still true for insomnia…and for Alzheimer’s, promising but still tentative).
Given that many of those 40 million migraineur Americans would prefer a pill over an injection (especially a self-injection), the race was on to develop an oral equivalent to this revolutionary treatment. And so began the Triptan Wars.
Do we really need 7 oral triptans (8 if you include the sumatriptan/naproxen sodium compound)? Doubtful. But one might as well ask do we really “need” the inevitable next “latest and yet greater” iteration of the iPhone? You be the judge. Yes, you…the physician’s patient/insurer’s client/economy’s consumer.
The economics of capitalism and the biology of natural selection have a lot in common: there may be an excess of entropy involved in the process, but eventually the more utilitarian option will dominate over those found to be inferior.
