Naratriptan is the most effective triptan?
In the US, we are lucky to have seven different triptans available in the pharmacies. Five of them – sumatriptan, rizatriptan, zolmitriptan, eletriptan, and almotriptan are considered to be more effective than the other two – naratriptan and frovatriptan. Frovatriptan has the longest duration of effect because its half-life is 26 hours. Its initial efficacy, however, is not as good as that of other triptans. Naratriptan has a half-life of 6 hours, while the leading five triptans, only 2-4 hours. Naratriptan is also considered to be less effective but it could be because the marketed dose is too low.
In an article in the latest issue of Cephalalgia Peer Tfelt-Hansen argues that naratriptan is as effective as sumatriptan. In fact, if you inject an adequate dose of naratriptan it works better than an injection of sumatriptan. Naratriptan, however, is not available as an injection, only sumatriptan is.
Naratriptan (Amerge) was introduced by the same company that made sumatriptan (Imitrex), the very first triptan. They decided to market it as a “gentle” triptan and selected a relatively low dose of 2.5 mg that had as few side effects as the placebo.
In clinical trials, 2.5 mg of oral naratriptan is less effective than 100 mg of oral sumatriptan. However, clinical trials have shown that 10 mg of naratriptan has similar efficacy to 100 mg of sumatriptan. Naratriptan, 10 mg had slightly fewer side effects than sumatriptan, 100 mg.
The author also mentions the conclusion of the 2004 review by the American Triptan Cardiovascular Safety Expert Panel: “Incidence of triptan-associated serious cardiovascular adverse events in both clinical trials and clinical practice appears to be extremely low”. For more than a decade now, all European countries have at least one of the triptans available without a prescription.
The practical implication of this information is that it is safe to exceed the FDA-approved dose of naratriptan. If taking one 2.5 mg tablet provides some relief, taking two or three at once will not result in dangerous side effects. I’ve also had patients tell me that they need to take a double dose of sumatriptan – 200 mg instead of 100 or 20 mg of rizatriptan instead of the maximum recommended single dose of 10 mg. In the US, eletriptan is available only in 20 and 40 mg strength. Some European countries have 80 mg tablets as well.
Since all triptans are now available in a generic form, three of them are very inexpensive and patients can bypass the insurance limits and pay out-of-pocket for additional tablets. That is if your doctor is willing to prescribe a larger number of tablets – many erroneously believe that triptans are a common cause of medication overuse, or rebound headaches. You can find naratriptan, rizatriptan, and sumatriptan in some pharmacies for less than $2 a pill.
You are absolutely correct in that the dose for naratriptan was driven primarily by business factors rather than clinical considerations, based on intel from KOLs in the 1990s. GSK developed sumatriptan, and Burroughs Wellcome had developed naratriptan, and I believe zolmitriptan was under development by one of the two companies. When GSK acquired or merged with Burroughs Wellcome, they had to decide as to what to do with naratriptan and zolmitriptan. The easy decision was zolmitriptan because it mostly closely resembled sumatriptan, which was being commercialized already by this point, and GSK sold off zolmitriptan to Astra Zeneca. What about naratriptan?
Naratriptan was viewed as more of a threat to the sumatriptan franchise at the standard 10-mg dose of oral triptans with good PK profile. And, as you pointed out, the SC version of naratriptan looked excellent. The business folks at GSK decided to developg naratriptan at an almost sub-therapeutic dose and capitalize on its long half-life even though they didn’t know what clinical benefits it would confer
Now, let me disagree with your statement that frovatriptan has a longer duration of action because of its long half-life. I have not seen any evidence linking an oral triptan’s half-life to its duration of action. Yes, there is probably a connection between half-life and duration of action for non-orals, but I don’t think there is one among orals. One piece of evidence is the Bomhoff study (Eur Neurol 1999;42:173-179) comparing the efficacy of rizatriptan and naratriptan. In this study, the recurrence rate for naratriptan was indeed lower than that for rizatriptan, but the time to recurrence was about the same. I believe recurrence is driven by initial response to an oral triptan instead of its half-life. You would think that if there was a connection between half-life and duration of action, the time to recurrence of naratriptan would have been much longer.
Thank you for this post, which is a good reminder to migraine patients that it may take several tries before finding the triptan that is best for them. I’ve tried five of the triptans and got the greatest relief from rizatriptan (Maxalt) and sumatriptan (Imitrex). I got okay results from frovatriptan (Frova) and zolmitriptan (Zomig). In my case, naratriptan (Amerge) was the only one that was NOT effective and gave me extreme fatigue and drowsiness. I appreciate you reminding patients that some of these valuable drugs are available out-of-pocket for just a few dollars per pill. I used to have terrible anxiety about exceeding the 9 pills/month allotted by my insurance. Now I let my insurance pay for rizatriptan while I separately purchase sumatriptan from Costco Pharmacy for less than $2/pill. These days I rarely need more than 9 pills per month (thanks to Emgality), but it’s nice not to have to worry if I do need more.