Abstract
Prof. Goadsby Has anyone stored up any question that they care to ask? I see an irresistible arm go up. Jim Lance.
Prof. James Lance Peter, I must say I agree completely with everything that Dr Cady said. That was a brilliant practical exposition that every severe recurrent headache is migrainous until proven otherwise. My question is; why do some patients not respond to a triptan? Has somebody tried to work out which of the patients have primarily a central generator which may not be susceptible to a triptan and how many have primarily vascular sorts of pain which are responsive? and what is the difference in the pathophysiology of patients that makes some responsive and some not?
Dr Michel Ferrari First of all, how do you define non-response? I think the only way to do that properly is to look at subcutaneous sumatriptan, because then you are rid of all the pharmacokinetic differences. With sc. sumatriptan, consistent non-response is extremely rare – only 4–5% when we looked a few years ago, and that is also the case with some of the oral triptans. Why do patients sometimes not respond in one attack, and then respond in another? Probably it is not the difference between patients, but the difference between attacks.
Prof. Carl Dahlof Even if you get a response to a triptan the first time, only 70–80% respond to a second treatment. We do not know the reason, but three in four people are more likely to respond, while a quarter are less likely to respond to a given treatment. I agree with Michel that over a number of attacks, sooner or later each will respond to a particular treatment. We have to find out why they are not responding each time.
Prof. Goadsby Thank you. Dr Watson?
Dr David Watson Do triptans cause headache?
Prof. Goadsby I am going to ask Dr Mathew (who is not on the panel but has a particular interest in the subject) to give the first response.
Prof. Ninan Mathew I do not know what the reason is. Sometimes patients who have a paradoxical response to an injectable triptan claim that their headache becomes worse. I do not have any explanation why.
Prof. Goadsby Prof. Diener?
Prof. H. C. Diener Yes, triptans definitely can cause an increased frequency of migraine attacks and daily headache in people who can afford to take them so often. In my country these are usually private patients; the others are saved by the price of the triptans. We have been doing a prospective study for 3 years. On average it takes 15 years to develop daily headache, about 2 years with sumatriptan, and one year with the newer triptans which are more brain penetrant in de novo patients who have not abused any other drug. It is not a major problem but it can occur and therefore you should limit the number of doses you prescribe each month. I think a practical limit would be less than 12 doses per month.
Question If sumatriptan does not work for a migraine, or if it recurs, can we use another triptan afterwards?
A panel member Well in the States you are not supposed to use a second triptan on the same day, but many of us have. In a patient who had had an oral dose of sumatriptan, I would rather use a subcutaneous dose for the second time which is permitted, but I think you could use a second triptan and it probably would not work on that attack.
Questioner Do you prefer to use another dose of the same or of a different triptan?
Prof. K. M. A. Welch Well contrary to what you heard earlier that a second dose of sumatriptan by injection might not work, I would say there are a few patients who do need a larger dose, so if I used sc. sumatriptan and it did not work, I would probably stick with the same drug and try it again.
I would like to comment on the last question about whether triptans cause headache. I have seen a few patients who have an increase in headache after sc sumatriptan. That might have something to do with an increased activity in the serotonergic system, but I have also seen a few patients who actually develop a headache from using a triptan. I agree with Professor Diener that if somebody gets to the point of using a triptan 5–7 days a week, there is a good chance that they will develop chronic headache and stopping the triptan may be necessary.
Dr Jerry Goldstein I have a comment, an admonition and a question. First I want to thank Glaxo Wellcome for asking me to come today, I was very honoured to have been one of the first investigators of sumatriptan in the United States way back when. I also want to say that I did not know quite why I was coming, but as the events of the day have progressed I recognize perhaps why I gave Stephen O'Quinn the opportunity to write several letters to Headache by virtue of an article that I authored. Third, it is important to note that sumatriptan, has many formulations and will certainly stand the test of time. I think one need not be afraid of comparing it to other triptans as we have done in our 5500 database.
A little admonition for Dr Dowson; as you know I am the person who sort of invented ‘Miss Lisa’ and I want to point out that when Mona puts on the ear muffs and then she puts on the glasses she has to have them both on at the same time to meet the IHS criteria for migraine headache.
Prof. Goadsby Thanks Jerry – an excellent example of neurologists being slightly pedantic. Thank you for those comments. Now a question from Switzerland.
Questioner We have many good reasons to use the triptans and one more is the low rate of allergies that they produce. However, there is a sulphur atom in sumitriptan and sometimes a patient claims to have a sulphur allergy and asks if she can use triptans. I have some patients who have sulphur allergies and have used sumitriptan without reactions, so I would like to know; is this a serious issue? My second question, is what is the sulphur atom doing in the structure there?
Prof. Goadsby Those are two interesting pharmacological questions and I am standing in front of a pharmacologist.
Prof. Dahlof : It is difficult to answer because that sulphonamide group which a number of triptans have is part of the molecular structure which defines the pharmacological properties of the class; it is just that particular chemical structure. I really probably cannot say more than that.
Prof. Goadsby I know that the sulphur in sumitriptan is related to the sulphur group being there. I will ask Reijo Salonen to comment.
Dr Reijo Salonen We list a precaution for sulphur because of the structure. From the database we have no evidence of cross-reactions between sulphur and sumatriptan, but once that precaution is on the label, it is impossible to get it off.
Prof. Goadsby A suitable cautionary note. The next question?
Dr Ed Messina I appreciated the comments about safety from Dr Welch and others, but it would be helpful to know the profile of people who have negative work-ups after getting chest pain or tightness after taking sumatriptan, because that would give us a better idea about whether or not to reintroduce the drug after our cardiology colleagues give us the go-ahead. Perhaps if we had a better idea of that profile we might end up using the agent more effectively in more people.
Prof. Goadsby That is a good question. I think we should take both European and US perspectives as they may differ. Michel?
Dr Michel Ferrari I cannot respond on the work-up, but what I can tell is that when you ask patients specifically about chest symptoms, up to 60% mention that once in a while they do have chest symptoms, yet none of these patients actually have any problems and go on taking it for 5, 6 or 7 years. So that is comforting and I do not see any relation with cardiovascular problems. We also looked at cardiovascular risk factors and their relation with chest symptoms and there was none.
Dr Alan Rapaport There is no standardized work-up in the States for that situation. In the beginning I was more cautious and I am still cautious about risk factors, but if somebody has some chest symptoms and I get nervous about it, I send the patient back to the primary care physician and ask if this patient can continue to take triptans. A whole variety of types of work-up follow, most of which cannot detect hidden coronary artery disease unless coronary angiography is included. So I think we are treating ourselves when we are overly cautious but sometimes it is good to do that anyway. After a negative work-up, the odds are very good that patient will continue to be able to take triptans without any problem.
Dr Ed Messina I appreciate these answers. I have been using this drug since it was released in the United States and I feel that it would be helpful if there was some publication – or if GW was willing to sponsor research – that would give us neurologists better guidance when trying to decide whether or not to use a triptan.
Prof. Goadsby It is a very good comment. I think that something will be published that sets out the information in considerable detail.
Dr Eddie O'Sullivan How does oxygen work in the role of the management of cluster headache and does nasal sumatriptan have a role in management?
Prof. Goadsby A double blind placebo control crossover study of nasal sumatriptan is just about completed and there will be an evidence-based answer soon. About oxygen; it is one of the interesting questions of cluster headache biology, and we are working on it but I do not really have a clear answer for you yet. I hear mutterings about vasoconstriction but I do not subscribe to the view that these things work simply as constrictors.
Let us take another question. I see Pramod Saxena, who developed the AV shunt model, without which nothing would have happened. We owe a debt of thanks to Prof. Saxena. I would like to give you the same applause that we gave everyone this morning, you did a splendid job.
Prof. Saxena Well, I'm speechless…
Prof. Goadsby Splendid, can we take the next question?
Prof. Saxena … but I would like to come to Michel Ferrari's comment this morning that the 5HT1D receptor agonist from Upjohn was ineffective in treating migraine but that the chest symptoms still occur. I am a simple pharmacologist and my idea is that we do not need 5HT1D activity. Should one advise GlaxoWellcome to try to develop a selective 1b agonist that will be effective for migraine without causing chest symptoms?
Dr Michel Ferrari That is going a bit too far I think. First of all, I did not say that the drug was not effective; that is just the rumour based on the abstract. The jury is out as to whether it is really effective or not, and why. The most important observation was that the selective 1d agonist can cause chest symptoms, showing me that you do not need 1b agonism for chest symptoms.
Questioner Can you use sumatriptan or other triptans during pregnancy?
Prof. Goadsby That's an excellent and recurrent question, very much for the clinicians. Andy?
Dr Dowson Currently the advice is not to use it during pregnancy or breastfeeding. There has been some surveillance and to my knowledge there have not been any cases of any untoward effects from taking sumatriptan during pregnancy.
Dr Reijo Sallonen We have a pregnancy register; 284 patients have been followed prospectively. So far there is no indication of teratotoxicity, but we need about 600 patients to be sure.