Abstract
Professor Goadsby
The workhorse of treatment for most acute medicine is the tablet. Carl Dahlof is a card-carrying pharmacologist and is Director of the Gothenburg Migraine Clinic. He is also one of the world's leaders in the clinical study of migraine and in clinical trial methodology. It gives me much pleasure to invite him to talk about sumatriptan tablets and suppositories. Carl?
Carl Dahlof
Thank you Peter. Can I start by thanking the organizers for the invitation to this prestigious meeting. As you heard, my task is to address our experience with the tablet and the suppositories. Over the years sumatriptan given orally has been tested in a wide dose range, from 25 to 300 mg; but it was soon found that 300 mg p.o. represents the very upper part of the dose–response curve, so the focus was on lower doses.
There are three different studies where 25, 50 and 100 mg have been compared with each other in placebo controlled trials, and I would like to address the results of one of those studies (1). In this trial almost 300 subjects in each group took active treatment, and the efficacy analysis showed that the 50 and 100 mg doses were almost indistinguishable. Both were significantly superior to the 25 mg dose from 2 h onwards (Fig. 1). Although we saw some differences with respect to efficacy at 2 or 4 h, there were no major differences in headache recurrence between the three doses tested—the figure was always around 30% (Table 1). Moreover, not only relief from headache was obtained; all doses reduced associated symptoms (Table 2). At higher doses, 50 and 100 mg, there was less need for rescue medication. Regarding adverse events, there was a trend towards an increase in pain and other pressure sensations with the higher doses (Table 3).
Efficacy of different doses of sumatriptan p.o. vs. placebo in the treatment of acute migraine attacks. (Data on file, GlaxoSmithKline) 25 mg, 50 mg, 100 mg vs. placebo: ∗P<0.05; 50 mg, 100 mg vs. 25 mg: †P<0.001; 100 mg vs. 25 mg #P<0.05.
Most frequently reported adverse events recorded following ingestion of sumatriptan tablet for acute migraine attacks, shown as percentage of patients reporting
(From reference (1) and data on file, GlaxoSmithKline.)
Relief of associated symptoms with placebo or sumatriptan p.o.
(From reference (1) and data on file, GlaxoSmithKline.)
Headache recurrence rates and times after placebo or different doses of sumatriptan
Headache recurrence: a headache that improved from grade 3/2–1/0 within 4 h of taking the first dose, but which then increased in severity to grade 3/2 within 4–24 h. (From reference (1) and data on file, GlaxoSmithKline.)
So in summary, all doses were found to be effective, but the 50 and 100 mg doses were very similar and slightly better than the 25 mg dose. With respect to tolerability, 25 and 50 mg were very similar, and a little better than the 100 mg dose. For that reason it was concluded that the best balance was obtained by the 50 mg dose, which is presently recommended.
There are five placebo controlled trials in which the 12.5 and the 25 mg sumatriptan suppositories were compared with placebo. The results are clear cut; a dose-dependent increase in efficacy was shown in all studies, both with respect to headache relief and pain-free at 2 h (Figs 2 and 3). The most frequent adverse event was nausea; while local and rectal adverse events were infrequent. The onset of action could be seen as early as 30 min.
Efficacy (headache relief at 2 h) of different doses of sumatriptan suppositories vs. placebo in the treatment of acute migraine attacks. (Data on file, GlaxoSmithKline.)
Efficacy (pain free at 2 h) of different doses of sumatriptan suppositories vs. placebo in the treatment of acute migraine attacks. (Data on file, GlaxoSmithKline.)
Now I will summarize all the placebo-controlled trials performed, looking at the mean percentage effect at 1 and 2 h for the tablets—there was no assessment at 30 min. In five trials, over 1000 patients were exposed to active treatment (50 and 100 mg doses). There was a clear superiority of active treatment, with a 32% headache response at 1 h and 59% at 2 h. In the trials of suppositories, efficacy was also assessed at 30 min; 45% obtained relief at 1 h and 67% at 2 h.
One way of comparing these different formulations is by calculating the therapeutic gain or ‘headache relief’—the gap between active treatment and placebo—as a mean for these different trials. From these trials it appears that the suppositories are a little faster in onset of action and provide slightly higher efficacy, although the 50 mg oral dose catches up at 2 h. The pattern stays almost the same at one and 2 h for ‘pain free’ (Fig. 4). Comparing the tablets, suppositories and sc. injection, the latter have better intrapatient consistency of response—about 80% obtain headache relief at 2 h in two out of three attacks. Within-patient consistency of response for 2 of 3 attacks occurs in 89%, 67%, 64% and 71% of patients with sumatriptan injection, nasal spray, tablets and suppository respectively. Within-patient consistency of response for 3 of 3 attacks occurs in 73%, 35%, 32% and 41% of patients treated with sumatriptan injection, nasal spray, tablets and suppository respectively. Thus, the injection is associated with higher intra-individual response consistency than the other formulations of sumatriptan. Looking at the therapeutic penalty (‘Number Needed to Harm’) the 100 mg tablet had a worse score, but both the 50 and 100 mg tablets were tolerated better than the suppositories. So there is a trade between efficacy and adverse events, most pronounced for the sc. formulation.
Therapeutic gains (pain freedom at different time points) recorded with different doses of sumatriptan tablets vs. suppositories in the treatment of acute migraine attacks in 17 studies. (Data on file, GlaxoSmithKline.)
Finally I shall address two studies in which sumatriptan tablets were compared with ergotamine, or where the suppository was compared with ergotamine-containing suppositories. In the first trial (2), sumatriptan 100 mg po. was compared to Cafergot® tablets (2 mg ergotamine and 200 mg caffeine). At 2 h, sumatriptan was significantly superior to ergotamine in providing headache relief, with respect to associated symptoms, and regarding the use of rescue medication. In the other trial (3), the 25 mg sumatriptan suppository was compared with the Cafergot® suppository (2 mg ergotamine+100 mg caffeine) with an optional extra dose of Cafergot® taken if needed at 30 min. The ergotamine suppository was more efficacious than sumatriptan (73% vs. 63%), but caused more adverse events such as nausea, so most patients preferred the sumatriptan suppository.
Now I would like to discuss a survey of migraine patients seen only by primary care physicians (4). We asked them about their use of acute treatments and found that there had been a dramatic switch from ergotamine to triptans. We also asked them about the subjective opinion about the efficacy of their treatments. Although 50% used analgesics regularly, only 10% considered them to provide good relief. Of those who still were using ergot, 77% thought it was useful, but the triptans were even more appreciated. Swedes suffer about 14 million migraine attacks per year; about 20% of these attacks are treated with a triptan (Table 4). In Turkey, I understand that citizens suffer about 110 million attacks per year, very few of which are treated with triptans. I sincerely hope that in the near future actions are taken to make this type of treatment accessible to even more migraineurs world-wide.
Varying frequency of triptan use in different locations
(From reference (6) and Dahlöf, C./SIFO 1997.)
So which triptan should we use? Prescribers should, I feel, let the patient try different triptans, and then decide for themselves which one they would like to use in the future. We have just finalized a preference study in Sweden (5) in which migraineurs who had been using oral sumatriptan were asked to test other triptans for two attacks each. Regarding satisfaction, 93% stated that sumatriptan provided rather or very good treatment efficacy and as to onset of action, 89% claimed that sumatriptan's was rather or very good. Accordingly, the majority opted to use sumatriptan in the future (Fig. 5). During 1999, sumatriptan made up about 75% of our triptan prescriptions.
Treatment preferences among 28 subjects exposed to three different triptan preparations for the treatment of migraine attacks.
So, to conclude, migraine has been a problem throughout history, but today there are new acute therapies and, more importantly, we do have different treatments and different formulations. If we use them correctly, tailoring the treatment to the patient, we will help to improve the lives of even more migraine patients in the future.
Thank you very much.