Findings from Recent Translational
and Clinical Research in Migraine
An interview from the 6th Annual Headache Research Summit at the NIH

Nabih Manih Ramadan, MD, FAAN, FAHS
Director of Strategy
Diamond Headache Clinic
Chicago, Illinois

The opinions contained within this commentary are solely those of Dr. Nabih Ramadan and are not supported or endorsed by MediCom Worldwide, Inc. or Endo Pharmaceuticals.

Introduction
On October 29 and 30, 2008, the National Headache Foundation held their 6th Annual Headache Research Summit at the National Institutes of Health in Bethesda, Maryland to present findings from recent translational and clinical research in migraine. The goals of the summit were to exchange information about advances in migraine research, promote translational research efforts, and support young investigators in their quest for answers to novel hypotheses relative to migraine disorder.

Dr. Nabih Ramadan, course co-director of the Summit, was interviewed for the Migraine Resource Network on November 14, 2008. His professional biography precedes the in-depth discussion about the Summit, translational research, and advances in migraine management.

Biography
Nabih M. Ramadan, MD, director of strategy at the Diamond Headache Clinic in Chicago, Illinois is also chairman of the Board of Trustees of Vista Health Systems. Dr. Ramadan is the immediate past vice president for strategic development at Rosalind Franklin University of Medicine and Science, and former chair of neurology and rehabilitation medicine at Chicago Medical School.

Dr. Ramadan received his medical degree from the American University of Beirut College of Medicine, completed a residency in neurology at the University of Cincinnati and a fellowship in cerebrovascular diseases at Henry Ford Hospital & Health System, and an MBA (health systems) with distinction from Keller Graduate School of Management. Dr. Ramadan is a fellow of the American College of Angiologists, the American Headache Society and the American Academy of Neurology. He is also a member of many national and international organizations including the American Academy of Neurology, the American Medical Association, the National Headache Foundation, American Headache Society, American Pain Society, American Society for Experimental NeuroTherapeutics, and Illinois Medical Society. Dr. Ramadan served as the medical editor for the ACHE newsletter and he is associate editor for Cephalalgia and Headache. He serves as an ad hoc reviewer for several journals including Stroke, Neurology, Journal of Cerebral Blood Flow and Metabolism, Journal of Clinical Pharmacology, Neurology Network Commentary, Annals of Internal Medicine, American Journal of Managed Care, Headache, and Annals of Pharmacotherapy.

Dr. Ramadan’s research interests include migraine, stroke, and chronic pain. He is in global demand as a speaker on topics related to headache, pain, stroke, clinical research, clinical trials methods, and neuropharmacology. Dr. Ramadan has authored and co-authored over 200 papers, over 40 book chapters, and has co-edited two books on headache.

Interviewer:
Dr. Ramadan, can you please provide us with a brief overview of the origins of the National Headache Foundation Research Summit and explain the Foundation’s original intent in developing an annual summit?

Dr. Ramadan:
The concept of the Headache Research Summit has evolved from what was originally an initiative held in conjunction with the regular meetings of the Diamond Headache Clinic Research and Educational Foundation. The Summit was intended to focus on the field's up and coming researchers and physicians, by providing them a forum for platform presentations for their research findings. During the Summit, the National Headache Foundation Lectureship Award, an award that recognizes the work of an outstanding physician in the field of headache, was also presented.

Interviewer:
Why is Summit 6 different and how have the goals changed over the past 6 years,
if at all?

Dr. Ramadan:
This year, the planning committee discussed the possibility of creating a dedicated meeting to achieve the same goals, supporting researchers in migraine, and the original initiative morphed into Summit 6. Summit 6 is the first of what will be separate and dedicated meetings held to achieve these goals, but with the added benefit of collaboration and grant support from the National Institute of Neurological Disorders and Stroke (NINDS).

The Summit now serves as a shared platform for discussion and for investigators to present notable and new research, but with one major change. The updated goal of the 6th Summit had the focus on translational research in migraine.

Interviewer:
What is translational research and how does it differ from traditional
clinical research?

Standard applied research is really the first generation of translational research and is unidirectional in nature. In this version, research observations were shared from the ‘bench’ or research lab to ‘bedside’ or the patient in the research clinical site. [Figure 1]

Figure 1. Translational Research, First Generation, Unidirectional: ‘Bench to Bedside’

Translational research is bidirectional in nature, which means observations are shared from research lab to clinic and from the clinic back to the research lab. For example, in the first generation unidirectional research model, the lab creates an animal model and observes responses in the patient based on animal data. In bidirectional translational research, an animal is modeled in the lab based on observations from the clinical environment. It is said that translational research takes the shared observations one step further, from ‘bench to trench’ and ‘back to bench.’ The ‘trench’ in this case is the community at large. This extends the observation from a small pool of clinical trial participants to the mainstream population at large in a community setting. [Figure 2] This new generation of translational research suggests that community-based health care practitioners are in a position to contribute to research simply by sharing and communicating observations made in real-world medical practice back to the research laboratory environment.

Figure 2. Translational Research, New Generation, Bidirectional: Bench to Community to Bench

Interviewer:
Who initiated this type of research reformation?

Dr. Ramadan:
The previous director of NIH, Elias A. Zerhouni, MD, proposed reformation of the General Clinical Research Centers (GCRC) Awards to Clinical and Translational Science Awards (CTSAs). He also embraced a new paradigm for research, to include the 3 P’s: prediction of pathogenesis, personalized and precise medicine, and preemption of disease before it occurs. These new ideas supported the NIH Roadmap Initiative.

These changes created a highly competitive environment. Grant awards are now more robust and extend for longer periods of time. Grant applications and proposals are also more cumbersome and time consuming to navigate and write. The premise of the CTSA grant awards requires that basic research be fully applicable to practical application in the clinic. Research without clinical value is no longer easily supported. The challenge, however, is that now research centers are expected to partner collaboratively with clinical sites in the community that offer a large pool of patients. In response to these changes, the number of awards has dropped from numbers in the hundreds to approximately 20. An interesting observation is that of the 20 CTS awards, many did not go to the top-tier, Ivy League schools. I attribute this to the fact that the awarded medical schools have greater access to community-based medical centers and diverse patient populations, satisfying the requirement for bridging lab discovery with community-based application.

Interviewer:
Do you interpret the reduced number of awards as a positive change?

Dr. Ramadan:
Yes and no. Yes, in that it really makes sense to conduct research with the goal of improved patient outcomes and not just research for its own sake. It is really all about taking research from the molecular level to practical clinical application, what we refer to as ‘practical clinical trials.’ We are now conducting research that extends beyond Phase II and III…to determine which findings apply globally. Previously, novel drug accessibility was limited to a specific population. With translational research, therapies are formulated and designed to possess global application. Unfortunately, the percentage of novel drugs that make it successfully into market remains at approximately 30%. Novel drug development is focused on targeted therapy. First, we identify the main culprit and substrate of the disease and subsequently develop a drug that possesses a high benefit to risk ratio. A major caveat to this sequence of events is that the more we become target-specific and avoid adverse effects, the more likely we’re going to be looking at a very discreet component of an illness. And we know that most manifestations of disease are not based on a single entity, be it gene, protein or receptor.

Interviewer:
After listening to all of the research presented at the Summit, which research area, in your personal opinion, holds the most promise for improving migraine therapies and why?

Dr. Ramadan:
I don’t believe it hinges on strictly one area of study, but a trio of areas, consisting of a three-pronged synergistic approach: combined use of genetics, molecular biology, and imaging technologies. The combined synergies are necessary to understand disease mechanisms, the culprit or primary substrate, and to advance discovery of targeted, upstream therapies.
 
Interviewer:
Some speakers likened today’s scope and magnitude of migraine research information to that of chronic pain research a decade ago. Can you explain what is meant by this statement?

Dr. Ramadan:
Pain research has progressed from a basic understanding of cellular and molecular mechanisms, many now confirmed via molecular imaging, to observance of these mechanism in the clinical environment.

Migraine science has developed in the reverse mode: from clinical observation of migraine to the recent understanding of basic molecular and genetic mechanisms of migraine. The more we learn, the more we begin to see the close correlation between pain and manifestation of migraine. Similar pain pathways, spinal and supraspinal, are at work for both migraine and chronic pain, as are inflammatory responses to ischemic endothelial injury, expression of various proteins, receptor hyperexcitability, ion flux, disease progression, and so on…there appear to be many similarities that overlap. It is important for experts in pain and migraine to exchange ideas and research discoveries. Right now we still need an improved understanding and appreciation of the full complement of mechanisms responsible for migraine and pain. This must occur not only to improve therapeutic management and slow disease progression, but to offer the ultimate goal: preventive therapies.

Interviewer:
Dr. Ramadan, what do you believe to be the greatest challenge facing migraine research today?

Dr. Ramadan:
The primary challenge is for us to increase awareness surrounding the disability and severity of migraine to encourage and stimulate adequate research funding. We also need to cultivate physician-scientists who can recognize the need for a study through clinical observation, and we are limited by the lack of clinical sites available that can serve as observational laboratories.

We have to remember that more than 80% of medical school students become practitioners in private practice. The leading medical schools may attract the basic scientists, but second-tier medical schools are now in the majority of those schools receiving NIH CTSA grants. The NIH grants are robust and offer a much higher percentage of funding for program development than other research grant options. They can be quite attractive to someone with a worthy hypothesis. One of the goals of our Summit is to bring together young investigators and seasoned scientists for information exchange and encouragement to pursue development of a research program.

Interviewer:
What do we have to look forward to in preparation for Summit 7, and what do you believe to be the next ‘big thing’ in migraine research?

Dr. Ramadan:
Our goal is to move forward with Summit 7 by sustaining the current Summit 6 model. The 2009, Summit 7 will be held in conjunction with the annual meeting of the Society for Neuroscience (SFN) in Chicago. This meeting will seek the support of the NIH as well. The SFN attracts an estimated 25,000 attendees, clinicians and scientists. It is a perfect venue for Summit 7 and will continue the momentum of elevating research in the field of headache and migraine study.

In answer to your question about the next ‘big thing’ in migraine, I suggest that migraine research is advancing so quickly now that it is difficult to speculate on what the next ‘big thing’ might be. Some ideas to consider are:

1. Is migraine a benign primary headache disorder or something more sinister? We need to consider recent findings related to white matter lesion formation as a response to chronic migraine.
2. Will we isolate genetic abnormalities responsible for common forms of migraine? We have already isolated genes defects responsible for familial hemiplegic migraine and need to pursue other types of migraine.
3. We need to develop and design interventions or therapies for upstream prevention. Preventive therapies should be one major goal of research, especially in consideration of disease progression. We are beginning to see how chronic daily headache can advance to migraine. Perhaps the progression may be due to level or load of stress. Is stress a genetic component?
4. That question leads to personalized medicine. Do certain people have a genetic or epigenetic predisposition to endothelial injury or response to endothelial dysfunction; to neurochemicals or proteomic changes that have a particular signature? The aim of personalized medicine is to match therapy to a unique patient profile based on individual chemophysiology, genetic, and environmental information. It is about predicting an individual’s susceptibility to developing a disease, disease progression, and the patient’s response to treatment.
5. In the best case scenario, we really need a predictive human model of migraine disorder based on signs and symptoms and diagnostic tests for confirmation. Identification of accurate disease markers, and note that I am using the plural form here, is critical to improving outcomes. Identifying a single marker is unlikely, as multiple mechanisms are likely responsible for onset of migraine disorder.

Migraine research is a fast moving target. As technology continues to rapidly advance, I am sure we will discover new methods of discerning factors responsible for migraine and its progression. Our Summit meeting is really meant to support the advancement of migraine research and to ultimately improve the care of patients afflicted by the disorder.

Interviewer:
Thank you for your time and expertise Dr. Ramadan.

Resources:

6th Headache Research Summit Program:
http://www.headaches.org/pdf/6th-Headache-Research-Summit-Brochure.pdf

National Institute of Neurologic Disorders and Stroke (NINDS)
http://www.ninds.nih.gov/

The Society for Neuroscience
http://www.sfn.org/