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AUTHOR COMMENTARIES - From Special Topics

Diener Professor Hans-Christoph Diener
From the archived Special Topic of Migraine & Other Vascular Headaches

Migraine is a form of neurovascular headache in which the brainstem structures that mediate pain are disinhibited, and vessels in the dura and the head dilate, stretching the nerves around the artery, thereby stimulating them into releasing chemicals that cause inflammation and pain. Migraine affects about 8% of the adult population; females are twice as likely as males to suffer an attack. The symptoms are a severe throbbing head pain, mostly one sided, with deterioration in physical activity. These effects are disabling.


According to our Special Topics analysis of migraine research, Professor Hans-Christoph Diener ranks at #8, with 110 papers cited a total of 1,329 times. One of these papers, "Guidelines for controlled trials of drugs in migraine: Second edition," (Tfelt-Hansen P, et al., Cephalalgia 20[9]: 765-86, November 2000), is ranked at #9 on our list of the most-cited papers in the past decade. Four other papers of Professor Diener's are on the list of the top 20 papers published in the past two years.

In Essential Science IndicatorsSM from Thomson Scientific, Professor Diener's work includes 158 papers cited a total of 3,024 times in the field of Neuroscience & Behavior and 222 papers cited a total of 2,650 times in the field of Clinical Medicine.

Professor Diener is the chairman of the Department of Neurology at the University of Essen in Germany.

In the interview below, he talks with ScienceWatch.com correspondent Simon Mitton about his research on the neurology of acute migraine.

How did you become interested in headache research?

I did my medical training at the Albrecht-Ludwigs-Universität in Freiburg. From 1970 to 1975, I studied in both the faculty of philosophy and the medical school, where I studied basic neurophysiology, neuropsychology, and psychophysics. Then I started to work in psychophysics and cerebellar physiology. Finally I went to the University of Tübingen where I finished my neurology training and got my Ph.D. in cerebellar physiology.

While I was there I got interested in headache. My chairman told me I should keep my fingers off headache because it has nothing to do with science! Nevertheless I started to work on medication overuse in headache. Then when I moved to Essen as professor of neurology in 1989 (that's when I became chairman here) I established a headache research group. We soon started animal experiments as a platform for neurological studies and we did all kinds of clinical trials.

Now I am the head of the German Headache Network, a collaboration which has 14 centers attached and is funded by the German Ministry of Education and Research.

In your career you have demonstrated a deep interest in a wide range of subjects. You have worked on cerebrovascular diseases, cerebellar disorders affecting the motor system, and headache. In the latter case, can you indicate your general areas of interest?

I have worked on the mechanisms and therapies of drug-induced headache. To some extent I have specialized in the action of migraine drugs, with some emphasis on clinical efficiency as determined from trials. I have been interested in the prophylactic action of beta-blockers and calcium channel antagonists in migraine. I have also worked with animal models for migraine, to investigate the role of cerebral vessels and neurogenic inflammation.

Could you tell me about the patient care and research environments in which you work?

Our inpatient department has 53 beds and a stroke unit with six beds. In company with the Clinic of Internal Medicine, we have an intensive care unit with 17 beds. Our physicians, nurses, therapists, psychologists, and social workers provide patient care. We have a large number of technical procedures available in our department

There are 11 research groups. A number of clinical studies are coordinated and executed at our Department. Our research contributes to provide the highest standard of patient care with evidence-based therapies.

How large is the network you are chairing?

The funding is 1.8 million euros ($2.6 million) per year. Eight of the 14 groups are here in Essen, and the remainder are in Berlin, Hamburg, Erlangen, Mainz, Aachen, and Munich. We cover everything from basic research with animals, epidemiology, and through to therapy studies.

How does the group compare to other European centers? It must be one of the largest.

No other institution is funded or functions in the way we do. So in that sense we are unique in Europe. There was recently a publication in the journal Cephalalgia about the funding of headache research in Europe. From that survey you can see that the highest spending is in Germany, and most of that funding is coming to our institute.

In this analysis covering your papers published since January 1997, your most-cited publication is a set of guidelines for controlled trials of drugs in migraine. Why has this second edition of recommended procedures made such an impact?

The purpose of having a set of guidelines is to create a level playing field so that from the point of view of medical science we can compare the results from different trials with confidence. That principle applies across the whole of biomedical research.

Everyone who does a clinical trial in migraine has to follow the guidelines we published. That is why it is so frequently cited. The first and second editions were the initiative of the International Headache Society Clinical Trials Subcommittee. The guidelines include the procedures to be followed for trial design, and the primary and secondary endpoints. They were adopted by EMEA, the European agency for approval of new drugs. The recommendations from EMEA are basically identical to those in the guidelines.

Is there an international dimension to these guidelines?

Yes, indeed there is. The guidelines were developed because of a need "to improve the quality of controlled clinical trials in migraine," and because only quality trials can form the basis for international collaboration on drug therapy.

With the current trend for huge multinational trials, there is a need for increased awareness amongst clinical investigators of methodological issues in clinical trials of drugs in migraine. These guidelines deal with those specific for this illness.

Ranked at #2 in your list of papers from this survey is a paper on drug efficacy (Tfelt-Hansen P, et al., "Ergotamine in the acute treatment of migraine—a review and European consensus," Brain 123: 9-18, 2000) one of your specializations. This review examines ergotamine in the acute treatment of migraine. What was learned in this review of ergotamine?

Ergotamine has been used in clinical practice for the acute treatment of migraine for almost 80 years, but there has been little agreement on its place in clinical practice. For this paper we worked as an expert group from Europe to review the pre-clinical and clinical data on ergotamine as it relates to the treatment of migraine. This is a review paper where we basically argued that evidence for the efficacy of ergotamine is not very good.

The paper is highly cited because it gives specific suggestions for the appropriate use of ergotamine. In essence, ergotamine, from a medical perspective, is the drug of choice in a limited number of migraine sufferers who have infrequent or long-duration headaches and are likely to comply with dosing restrictions. But the review shows that for most migraine sufferers requiring a specific anti-migraine treatment, a triptan is generally a better option from both an efficacy and side-effect perspective.

Ranked at #3 on your list is a paper on topiramate and the beta-blocker propranolol in migraine prophylaxis (Diner HC, et al., "Topiramate in migraine prophylaxis—results from a placebo-controlled trial with propranolol as an active control," J. Neurol. 251[8]: 943-50, 2004). What's the story here?

The mode of action for most drugs used in migraine prophylaxis is unknown. In addition, a powerful placebo effect exists in migraine prophylaxis studies. When we did this study the most frequently used drugs for migraine prophylaxis were beta-blockers, anticonvulsants, serotonin antagonists, and calcium channel blockers. The efficacy of these drugs is at best 50%, and in addition they have side effects that may be unacceptable to some patients. Therefore, the search for further prophylactics for migraine was the driver behind this paper.

Why did topiramate in particular attract your attention?

In July 1995, topiramate received approval in the UK as adjunctive therapy for the treatment of partial-onset seizures in adults. Topiramate is currently approved as a monotherapy for epilepsy in more than 40 countries. Its action on neurotransmitters suggested that it might be an effective compound for controlling the frequency of migraine attacks.

We conducted a randomized, double-blind, multicenter trial to evaluate the efficacy and safety of topiramate versus placebo for migraine prophylaxis with propranolol as an active control. The outcome was that we demonstrated that topiramate has about the same efficacy as propranolol. But, and this is important in terms of citations, we added a new drug to the toolkit available for the treatment of migraine.

Neurology is the focus of paper #4 (Kaube H, et al., "Acute migraine headache—possible sensitization of neurons in the spinal trigeminal nucleus?" Neurology 58[8]: 1234-8, 2002). What is the main result in this contribution?

That paper reports an investigation, using a novel blink reflex, of 17 migraine patients within six hours of an acute one-sided attack. Our result suggested that during a migraine attack the central trigeminal neurons are temporarily sensitized.

Paper #5 (Katsarava Z, et al., "Incidence and predictors for chronicity of headache in patients with episodic migraine," Neurology 62[5]: 788-90, 2004) is concerned with the incidence and percentage of transition from episodic migraine to chronic migraine. What are the findings here?

We followed 532 patients with episodic migraine for one year. 14% of the sample developed chronic headache, defined as more than 15 days per month.

Medication overuse coexists in the majority of patients with chronic headache and improves after withdrawal from the overused headache medication. This suggests a causal relationship between the medication overuse and chronicity of headache.

Our study was in line with these findings showing that patients who overused their headache medication had a high risk of developing chronicity of headache. One-third of patients, however, developed chronic headache without medication overuse, suggesting that medication overuse is an important but not the only factor determining chronicity of headache.

Finally I'd like to ask you to comment on #8 (Diener HC, et al., "Efficacy, tolerability and safety of oral eletriptan and ergotamine plus caffeine [Cafergot®] in the acute treatment of migraine: A multicentre, randomised, double-blind, placebo-controlled comparison," Eur. Neurol. 47[2]: 99-107, 2002), which examines the comparative efficacy and safety of intravenous aspirin in the acute treatment of migraine.

This is another of our papers examining what works and what does not work in the treatment of migraine. Here we looked at intravenous treatments, which have to be used in cases where oral treatment in the emergency room is ineffective because of vomiting or diarrhea. We conducted the study in 17 centers in Germany with a sample of 275 patients who had suffered acute attacks.

In summary, we found that subcutaneous sumatriptan and intravenous lysine acetylsalicylate are effective treatments for patients suffering from migraine attacks. Sumatriptan is more effective, but resulted in more adverse events.

Prof. Dr. H. C. Diener M.D., Ph.D.
Department of Neurology
University of Duisburg-Essen
Essen, Germany
  

Professor Hans-Christoph Diener's most-cited paper with 265 cites to date:
Albers GW, et al., “Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III) randomised controlled trial,” Lancet 362(9397): 1691-8, 22 November 2003. Source: Essential Science Indicators from Thomson Scientific.


2008 : March 2008 - Author Commentaries : Hans-Christoph Diener