Abstract
Professor Goadsby
In the final session before lunch we will hear overviews of the clinical trial results of sumatriptan. The first presentation concerns the injectable form. The next speaker is Dr Michel Ferrari of the Leiden University Medical Centre. While his own contributions to the biochemistry of migraine were important, the contributions of his group to the genetics of migraine were seminal and represent one of the great things in migraine that have happened during the last 10 years. It is a particular pleasure for me to introduce Michel Ferrari.
Michel Ferrari
Thank you, Peter, for your kind introduction. When we ask patients; ‘What do you really want from your headache medication?’ we hear that they want rapid and complete relief from all their migraine symptoms, for nausea and vomiting are also outstanding features of the disorder. The second need is for a consistent predictable effect, so that they can be confident that each time they use it, it will be effective. The third item is sustained relief.
There is delay in the oral absorption of most oral medications taken during attacks; and we all know that a rapid rise of the plasma concentration is very important to obtain high relief. So what is the logical choice for therapy? Surely it should be parenteral administration. Sumatriptan has a peak plasma level 15 min after sc. injection, which is exactly what is needed. In clinical terms, I have shown (1) that over 70% of patients respond in the first hour and the pain-free figure is close to 50% within 1 h (Figure 1). Roger Cady's study (2) also showed a statistically significant benefit compared to placebo, even at 10 and 20 min (Figure 2).
Percentage of subjects achieving ‘headache response’ at 1 h after treatment subcutaneous sumatriptan 6 mg, all differences vs. placebo P<0.001 (from [1]).
Time course of subjects achieving headache relief (mild or no pain) after treatment with sumatriptan 6 mg sc, ∗P<0.001 (from [2]).
Three problems remain; some patients do not respond within an hour; and some of those that do experience headache recurrence. We wondered if it would it be useful to repeat the 6 mg dose of sumatriptan for those who had not responded at 1 h. The result of our placebo-controlled trial (1) was negative so it is extremely unlikely that there would be clinical benefit (improvement rate 6%; CI. 5–17%) (Figure 3). On the other hand, if after a few hours the headache recurs, you can treat this recurrent headache effectively; 84% will respond to a second dose (Figure 4).
Clinical effect of a second dose of sumatriptan in subjects who had not responded to an initial dose by 1 h. The second dose appears not to be useful (from [1]).
Beneficial effect of a second dose of sumatriptan sc. by 1 h in subjects who had responded to an initial dose, but in whom headache had recurred (from [1]).
The third problem concerns the comparison of headache recurrence rates between drugs. It is probably misleading to present figures for headache recurrence without taking into account the degree of initial relief and the need for analgesics as escape medication. The methodological issues with this point can be solved by using the composite measure ‘sustained pain free’, which implies that there is no pain by 2 h post-dose, there is no recurrence and analgesics are not needed within 24 h. So we ask what proportion of patients require only one single dose to abort the attack within 2 h and for 24 h more as that it is a useful measure. Comparing sc. sumatriptan and DHE, sumatriptan provides higher initial relief rates, but the rates of headache recurrence are higher (Figure 5). Despite the apparently sustained relief from DHE, its later onset of action leads to the situation that patients with DHE use far more rescue medication than do those using sc. sumatriptan. Using the composite measure, sc. sumatriptan is obviously better than DHE. Of course every effective drug has its downside, and sc. sumatriptan does have side-effects such as injection site reactions, but in general the adverse events are mild and of short duration (Table 1).
Percentages of subjects achieving a 2 h headache response, experiencing recurrence before 24 h, requiring rescue medication within 24 h, or obtaining a sustained response when treated with sc. sumatriptan or DHE 1 mg + 1 mg (from [4]).
Percentages of subjects experiencing various adverse events after treatment of migraine headaches with sumatriptan 6 mg sc. or placebo (aggregate from several trials)
There is debate on whether chest symptoms are really due to coronary vasoconstriction. The best evidence is that in most patients, chest symptoms are not due to vasoconstriction. For instance, one specific 5HT1D receptor agonist has been shown to have exactly the same side-effects as the other triptans, so the ‘triptan sensation’ is not due to 5-HT1B receptor activation and may reflect neuronal stimulation rather than vasoconstriction.
The advent of sc. sumatriptan showed us that it is safe to administer a triptan during an aura, although remarkably it does not prevent the ensuing headache. For practical reasons, therefore, I advise delay in the use of sumatriptan until the headache has started. We interviewed many patients who claimed that sumatriptan was ineffective and found that most of them had used it too early; when they delayed its administration in future attacks, it worked.
How is sc. sumatriptan performing in clinical practice? Well, one of my PhD students, Dr Visser, studied 735 migraine patients over 2 years and found that it was extremely well tolerated and highly effective. Nearly 90% of patients became pain free in 2 h; consistency was high with 90% of attacks treated effectively; and 75% of patients were still using sc. sumatriptan after 2 years. World-wide experience with sc. sumatriptan has been gained from more than 25 000 patients in clinical trials suffering over 100 000 attacks. In the population at large, more than 60 million patients have treated over 360 million attacks.
So to summarize, sc. sumatriptan provides the fastest and most complete relief, which is what patients want most, consistency of effect, an important but often neglected aspect, and a huge clinical database of experience. It has had an enormous impact on scientific and clinical scientific research. But there are also some disadvantages, of which the first is recurrence—although this is a problem for all members of this class. My advice is to warn patients that they may experience recurrence, so if it happens they are not as disappointed as they would be were it to return without warning. Adverse events are more frequent and perhaps transiently intense—but again, informed patients tolerate and accept them well.
I like to give advice, even for free, and my advice to GlaxoSmithKline is to get rid of the fixed volume in the auto injector, because 6 mg is too much for many patients who go on to experience adverse events and may stop using it. Often, 3 or 4 mg would suffice. As to its place in clinical practice, to me it is still the logical choice. But I strongly recommend an alternative needle-free device that offers a flexible dose.
Thank you.