Migraine – An interview with Professor Timothy Collins

Professor Timothy Collins, interviewed by Dr Kieran Walsh

This article is based on a podcast that was recorded by the BMJ Best Practice team. In this article, the Clinical Director of BMJ Best Practice, Dr Kieran Walsh interviews Professor Timothy Collins, Associate Professor of Neurology at Duke University Medical Center in the USA and author of the migraine topic on BMJ Best Practice.

BMJ Best Practice offers evidence-based, continually updated and practical knowledge that will help you make better clinical decisions.  

Interviewer: Migraine is a common problem. A survey of over 4,000 people in England showed that 7% of males, and 18% of females experienced migraine with or without aura within the last year.

Attack rates were 1 or more per month in most people, and most experienced interference with activities of daily living in 50% or more of their attacks. So, this is an important problem as well as a common one.

To tell us more about migraine, we have been delighted to interview Professor Timothy Collins who is Associate Professor of Neurology at Duke University Medical Center in the USA.

So, Professor Collins, tell us, what exactly is migraine?

Professor Collins: Well, migraine is a process that we don’t fully understand, but it causes a painful throbbing sensation in the head in most people, and it almost always has some combination of nausea, sensitivity to light, or sensitivity to sounds.

A lot of people have changes in their vision before their headache, or during the headache that, combined with the other symptoms, really interferes with their ability to function in their daily life.

We don’t fully understand this process that we call migraine, but it’s clearly caused by abnormal discharges of a group of nerve cells in the brain stem that result in this increased sensitivity to pain and other sensations, and even results in a change in how patients perceive the pain that they’re experiencing.

And all of this results in varying levels of disability on the patient’s part that makes them pretty miserable during the process of this thing that we call a migraine.

Interviewer: Okay, thank you. And I guess, first and foremost becomes diagnosis. Tell us about recent advances in diagnosis, if there has been any?

Professor Collins: The diagnosis of migraine is really based entirely on information we can get from the patient about what they’re going through; the characteristics of their pain, where it hurts, what kind of symptoms they have associated with the pain.

We have to get this information really from just talking with the patient, and at the same time we’re also looking for any clues that there may be something more serious going on; complaints that aren’t part of a regular headache process, things like weakness or loss of consciousness, or double vision.

Unfortunately, we don’t really have test for migraine. We can't put a patient in a scanner like an MRI scanner or a CT scanner, and diagnose the migraine. Really, the advances and our diagnosis of migraine are really the advances in making sure that they don’t have some other medical illness, like tumour, or multiple sclerosis, or aneurysm.

So, after we talk with the patient, the testing that we’re doing is really looking for other diseases that might mimic migraine.

Interviewer: Okay, thank you, that’s helpful. And staying on the diagnosis theme, I wonder what are the common pitfalls in diagnosis?

Professor Collins: Well, I think the most common difficulty in diagnosing migraine is either not having the time to talk with the patient about everything they’re going through, or not getting accurate information from the patient in terms of the different problems that happen during a headache attack.

Sometimes it’s just lack of awareness on the provider’s side in terms of what the best questions are to ask for that. If you don’t have good information about the symptoms the patient’s having, and whether or not there’s any of the what we call red flags present that would make us do additional testing, it can be difficult to make an accurate diagnosis.

The red flags are the things that really tell the provider that there’s a more serious problem. So, things like episodes of loss of consciousness, asking specifically about whether or not they get weak, paralysed with their headaches, or how long ago the problem started are important questions, and neglecting some of those questions can lead the physician as the provider down the wrong path in terms of diagnosis.

Interviewer: Okay, great, thank you. And, moving on to management now, can you tell us about recent advances in management?

Professor Collins: Well, the most recent advance in management is this new category of medications for migraine prevention that has been developed over the last 10 years that are custom antibodies against a protein called calcitonin gene-related protein, or CGRP.  

Three of these new products were recently FDA approved for use in the United States and are fairly remarkable in terms of ease of use and lack of side effects. They appear to have relatively minimal to no side effects. There are no contra-indications to their use compared to our older medications, many of which were not safe in certain populations.  

People with poorly controlled high blood pressure or people with a history of coronary heart disease or stroke couldn’t take some of our older medications because they were felt to be too risky. And those risks really aren’t present in this new group of medications.

And so, there’s actually at least one more medication in this category that we’re expecting to come on the market in the near future. So, we’re expecting good things with these new medications in terms of safety and effectiveness.

Interviewer: And one new drug that’s mentioned in the BMJ Best Practice topic on migraine is erenumab. Is that a drug from that class of medications?

Professor Collins: Yes, that’s exactly right. Erenumab is a humanised antibody that blocks the receptor for this protein called CGRP. So, this antibody actually sticks in the receptor and prevents CGRP from binding.

It first came on the market in the United States in June of 2018 and has reasonably good effectiveness in terms of decreasing the number of headaches that patients have in the course of a month.

It’s an injectable medication, and currently is marketed in a spring-loaded autoinjector that the patient uses at home once a month as a prevention medication for their headaches.

Side effects that have been reported with this are relatively minimal. In a clinical trial, they actually compared the drug to a placebo, and the only side effects that occurred more often in the drug group, compared with the placebo, were a redness of the injection site, constipation and muscle spasms. And those two were in the range of about 1% of patients that were receiving the drugs. So pretty minimal side effects compared to many of our older prevention medications.  

Interviewer: Okay, thank you, that’s helpful. And I’m guessing that this drug wouldn’t be for everybody with migraine? It would be for select groups of patients? Is that correct, and if so, what would be the criteria for prescribing it?

Professor Collins: So, in the United States, it’s approved for the prevention of migraine, and there’s not really much in the way of restrictions on it, in terms of how bad the migraines have to be.

It is significantly more expensive than the older medications, which are all really generic and inexpensive, and so at least here in the United States, it’s been restricted by the insurance companies to patients that have already failed at least two of the standard prevention medications like topiramate or valproate, or amitriptyline.

In terms of contra-indications, the only people that we really are not giving the medication to at this point, is women who are pregnant or who might become pregnant in the next six months. It’s not fully understood whether or not this new medication has any effects on pregnancy. It is an antibody, and some antibodies do cross the placenta into the developing foetus, so we’re not putting pregnant women on it right now.

Erenumab also has a very long half-life. It takes our bodies about 28 days to eliminate half of the dose that we receive, and so the medication is going to be present for 3 to 4 months after a single dose, which makes it difficult to stop quickly if someone discovers they’re pregnant; they’re still going to have a significant exposure for the first half of the pregnancy. So that’s probably the biggest restriction right now that we’re looking at.

Interviewer: Okay, thank you, that’s really helpful. And continuing with management, can you tell us what are the common pitfalls in management?

Professor Collins: Well, I think there is two or three things that we see over and over again in our headache clinic. The first one is more of a patient issue. For prevention medications, if you’re trying to decrease somebody’s headache frequency, you really have to try the medication for six to eight weeks before you can say that it’s not doing anything.

Many patients are very reluctant to wait that long to see if the medication is working. They all want something done immediately about their headaches, and prevention medications don’t really act quickly.

The second thing that we see frequently, is more of a provider issue in terms of not offering the patient a second or third medication to try for prevention.

There is a long list of medications that we know are effective for headache prevention based on randomised clinical trials and none of those medications work for 100% of patients. In fact, at best, any single prevention medication will work for 60% or 65% of the people we give it to.

And so, it’s really important to have a list, or a plan of what you’re going to do if this first medication you give the patient doesn’t work, what do you have teed up for the second and third try, because you may need to try two or three before you find one that works.

The same issue is true for acute therapy, in terms of helping out each headache attack when they have it – the same issue of not trying more than one medication is a problem that we see in our clinic frequently.

The third thing that we see frequently is that unfortunately all of our treatments for a headache have the possibility of side effects, and we have to talk upfront with our patients and set expectations that you know this medication works very well for some patients, but it can have side effects.

And make sure the patient is understanding that if they have a side effect, we can take them off and try something else and see if we can find something that works as well for their headaches, but without the same side effects so that they can tolerate it better.

Interviewer: Yes, that’s very helpful. And moving on to another topic that came up in BMJ Best Practice on migraine was the use of valproate as a preventative agent, and that’s being used less and less. Can you tell us a bit about this?

Professor Collins: Yes, valproate is actually a really good medication for migraine prevention, and it’s something that’s been used really for 20 years, or a bit more, for migraine prevention. The problem with valproate, is that first of all, you really have to check laboratory monitoring while the patient is taking valproate.

In the epilepsy population, valproate has been reported to cause bone marrow suppression with low white blood cell counts, and it’s also been reported to cause elevation of the liver function tests. And so, we really have to monitor for that when we first put patients on valproate.

So that’s inconvenient for both the patient and their provider. The patient has to come in every couple of weeks to get blood drawn for lab tests, and it bumps up the cost of care for the patient.

Valproate causes weight gain in 10% to 15% of people that take it. This is really unpopular with patients. Many of my patients have already looked up things on the internet that they can take for their headaches, and they come in and tell me, “I’m not going to take this medication because it causes weight gain.”

And convincing people to try the medication, even though it might cause weight gain is very difficult. As you noted at the start of our talk, migraine headache is about three times as common in women as men, and women are fairly sensitive to issues like weight gain, and they get pretty upset with us if we put them on a medication that makes them gain weight.

And then, the third problem with valproate is that it causes really severe birth defects if someone conceives while they’re taking valproate. It dramatically increases the risk for spina bifida, which is a very severe birth defect.

The problem with spina bifida is that the birth defect that we call spina bifida starts out within the first 30 days of pregnancy, and so it’s often before someone even knows they’ve conceived. So if they’re taking valproate and get pregnant, by the time they know they’re pregnant the damage is pretty much already done if they’re going to have a problem with it. So, we have to be cautious just for that standpoint in putting women on valproate.

So, when you combine all of those issues together, and then compare it to another older medication, like topiramate, which causes weight loss as a side effect and doesn’t have to have laboratory monitoring, people are really reluctant to take valproate at all.

Interviewer: Okay. Thank you very much Professor Collins. We hope that this has been helpful, and we hope users will be able to put what they’ve learnt into action to better care for affected patients.

If you want to find out more, click on the link to look at the migraine topic on BMJ Best Practice https://bestpractice.bmj.com/topics/en-gb/10


Competing interests

TAC was an unpaid site PI for the Alder study ALD403-CLIN-011 (monoclonal Ab against CGRP as treatment for chronic migraine), which ended in July 2017. TAC served as a paid consultant for Eli Lilly Co. in November 2016. In 2017 he served as a paid consultant for Alphasights, a global healthcare consulting organization, regarding migraine headache diagnosis and treatment. He has provided expert testimony regarding headache disorders for a legal case in 2015, and expects to be paid to provide expert testimony on headache disorders in 2018 for a legal case relating to the diagnosis, treatment, and standard of care for headache disorders.