Rewriting Migraine: From Misunderstanding to Medical Breakthroughs

Shahid Akhter, Consulting Editor, FEHealthcare, spoke to Dr. Stewart J. Tepper, VP, The New England Institute for Neurology & Headache, and Professor of Neurology, Geisel School of Medicine at Dartmouth, about the global burden of migraine, breakthroughs in treatment, and their potential impact in India.

 

Migraines are often misunderstood and underestimated. From your global perspective, how do you see migraines impacting patients’ quality of life and productivity on a large scale?

Globally, migraine has been evaluated by the World Health Organization and ranks among the top five disorders in the Global Burden of Disease study for years lived with disabilities. What this means is that people experience recurrent, disabling episodes of migraine, and because it typically lasts a lifetime, the number of years impacted is extremely high. If you combine that with the frequency of migraine in the population, the data from India is striking. Dr. Chaudhary recently published a paper showing that one in four people in India suffer from migraine, which is a quarter of the population. The economic, social, and personal impact is huge, yet still tremendously underestimated. 

The positive development is that, in the last decade, we now have migraine-specific treatments that offer maximum effectiveness with a minimum number of side effects. However, there is an imbalance: while treatments have advanced, recognition, diagnosis, and appropriate treatment of migraine—the most common neurological disorder—are still lagging behind.

 

Over the years, what significant advancements have been made in migraine management, and how have they changed the standard of care?

I think it's most useful to talk about the current situation and what we've learned about how migraine develops. Migraine starts in the brain, but the pain mechanisms occur outside the brain, in the meninges. What we've learned is that a set of chemicals is released during a migraine, and these chemicals are what trigger the pain. In simple terms, the brain turns on, chemicals are released, they cause the pain, and that pain signal is integrated. 

Where things have changed is that we now have treatments that target these chemicals. Among them, the most important is a chemical called calcitonin gene-related peptide, or CGRP. CGRP is released in a migraine, and it binds to a docking station or receptor, which leads to the pain. There are oral drugs that either block the CGRP from landing, monoclonal antibodies that block the CGRP or the receptor, and drugs that prevent the release of CGRP. There are also drugs that prevent the signal from getting back into the brain. This has created a menu of treatment opportunities.

 

Can you explain the CGRP-based therapies and gepants and how they are revolutionizing the management of migraines?

Migraine has three steps. The first step is when the brain turns on, which generally occurs one to three days before the pain begins. This means the migraine attack is much longer than the headache phase. During this early phase, people experience symptoms even before the pain starts.

The second step occurs when the brain sends a signal outside the brain to the meninges.CGRP is one of the chemicals that is released, and it binds to the docking station, causing the blood vessels to dilate or get big, causing inflammation. This combination of the inflammation and the blood vessels getting big is what hurts.

In the third step, the signal goes back into the brain and is processed. This leads to symptoms such as nausea, sensitivity to light, sensitivity to noise, and pain.

The dilation and inflammation of blood vessels in the meninges is like meningitis. It's not infectious meningitis, but it's meningitis. And every time a person gets a migraine, they're experiencing this kind of meningitis, and that's why the condition can be so severe and disabling.

 

 How do these newer therapies differ from traditional treatment in terms of efficacy and patient outcomes?

The older treatments were used on an as-needed basis for acute treatment, mainly to terminate an attack. The two big, older treatments were non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, and triptans like sumatriptan or rizatriptan.

Triptans constrict the blood vessels that CGRP dilates. Because of this, triptans cannot be used in people that have blood vessel or vascular disease. They just work on the blood vessels and the release of the CGRP, but they don't work on the inflammation. The anti-inflammatory drugs, on the other hand, work on the inflammation but have no effect on the blood vessels.

The new treatments, the gepants, block the CGRP from landing by sitting in the docking station. By doing that, they prevent the blood vessels from dilating, as well as prevent the inflammation. The wonderful thing about Gepants is the side effects are minimal. Most people hardly notice they have taken the medication. This allows people to treat their migraine very early and return to normal function without a consequence.

 

Are there any upcoming innovations in migraine therapeutics that you are particularly excited about?

Well, the most important priority is to make anti-CGRP therapies accessible to all the countries of the world. That's a big task, and in many countries it’s only just the beginning. For India, the first Gepants will become available in October. Some of these medicines are for acute treatment of migraine, while others prevent migraine if taken frequently. Some can do both. There’s an opportunity to broaden access of these very important therapies to people worldwide.

Once the anti-CGRP therapies are established as the first line worldwide, the next question is, are there new targets that could be as effective, as safe, and as tolerable in the people that don't respond to the anti-CGRP therapies? And there are some targets that are being actively studied right now. We're looking at a three- to five-year horizon for those.

 

Migraines significantly impact productivity, with patients averaging 5.9 missed workdays per month in India. How do you see effective migraine management influencing workplace productivity?

The problems with the older treatments are multiple. Many people don't get pain-free; they experience side effects, or they can't use the treatment when they need to restore normal function at work. This results in either missing work or being at work and not being fully productive, and in some cases the headache comes back. The new treatments can be taken very early; they're not habit-forming. They don’t have side effects, and they’re pain-free. That improves work productivity and reduces work loss, which it has done in the rest of the world. In fact, the new group, the Gepants, can be taken before the pain begins. Remember, there's a one- to three-day period: the brain turns on, and people have symptoms but no pain. Some of the symptoms are called prodrome; others are called aura. If patients take a gepant during that period, they may not progress to the pain stage. And since they don't have any side effects, I tell them you don’t even need to worry about whether you would have gone on to develop a severe migraine. They can prevent having the pain part of the migraine occur, which is pretty amazing!

In India, only work loss has been evaluated. That's absenteeism, but there's also presenteeism, which means they're at work and they're not firing on all cylinders. The economic loss per person has been estimated in India at Rs 9000 a year, which for the country is 19,000 Crore, and that's 4.75% of GNP. So, the economic consequence just from the absenteeism is huge, and that doesn't take into account the time when people are less productive. It also doesn't take into account the number of people who aren't working but who also can't perform at home or at social activities. Migraine has a pervasive effect on people, and the outcomes that need to be measured have to do with returning to function. What really matters is people’s return to function with an improved quality of life.

 

Many migraine sufferers feel isolated or misunderstood. In your experience, how important are patient education and awareness?

It is very important. Migraine is three times more common in women than in men, making it a female-predominant disease. There has not been a good biomarker for migraine, and so it tended to be dismissed, even though it's the most common neurological illness. Today, we can see changes in functional imaging on MRI scans, and we have identified chemical targets that have resulted in extraordinary treatments. It's a big change in how neurologists regard migraine, and there has been an increasing understanding of the possibility that it is remediable for patients. We need to do a better job of educating both the general public and the government and regulators, along with our colleagues in medicine.

 

 Do the advancements in migraine treatments like the CGRP therapies have broader applications in the field of neuroscience?

It's instructive that we were able to find a target that was so pure. Targeting that particular chemical has resulted in such profound change that it implies there may be other hidden targets that can be used in neurological illnesses, for example, in Alzheimer's. There may also be other similar targets in migraine itself. I have been doing this for a long time. I've been in headache management for decades, and this has been the most exciting time. And, it is what I always say: it's translational research come to life. The proposal that CGRP played a role in migraine came out in the late 1980s, and it has taken all these years to develop these treatments. My encouragement to my younger colleagues is to stay committed. Future targets are likely to be developed; while the process takes time, it's worth it.

 

What is your vision for the future of headache and migraine management, particularly in countries like India?

The International Headache Society published a paper early this year in which they set a new goal from a clinical therapy standpoint, which was migraine freedom. It wasn't just pain relief—a single outcome—it was freedom from migraine. In my practice, that's what I tell patients. I want you to be in the circumstances in which you come back to me and tell me that you forget you have a migraine. Occasionally you'll get a breakthrough that needs additional treatment. But what I give you, I don't want you to have side effects, and I want the frequency with which the migraine knocks on the door to be very infrequent and not have any impact. That's the goal for the future, and we're already achieving that in a large number of patients, at least in the United States, with the new treatments.

As these treatments are approved, the same thing will happen in India. It is the most hopeful time I've had in my career as a headache medicine specialist, because, as I was saying earlier, a decade ago, if I had one or two patients a month who said to me, "My life has completely changed," I was doing very well. And now I hear that almost every day when I'm in practice. I just had a patient write to me yesterday and say, "I'm so thankful my life has completely changed." Thank you for prescribing these medicines. I don't have any side effects. Please renew my prescription. So, I'm very, very optimistic and hopeful.