Professor Paul Rolan is a clinical pharmacologist, drug developer and pain management physician and researcher based at the University of Adelaide. I was fortunate enough to have a chat with him in the lead up to Migraine Awareness Month about how his work intersects with migraine. Professor Rolan’s website is https://www.profpaulrolan.com.au/
Katrina Szetey: Paul, it’s lovely to meet you. I was wondering if you could tell me a little bit about yourself and maybe your work and your research interests.
Paul Rolan: Yes, I got into the migraine area through a very circuitous path, most people have got there by being neurologists. I trained in the area of clinical pharmacology, which is a branch of medicine, which is really looking at the general principles of the way medicines are developed and used. And after qualifying I went to work for a pharmaceutical company in the United Kingdom. It was a very unusual pharmaceutical company, The Wellcome Foundation, because it was the only one that was owned by a charity, and therefore it wasn't the same commercial model as others, it had a very different kind of culture. It was a fantastic place to work.
One of the projects that I was given was to do all the early clinical development of the second triptan to be developed, that was zolmitriptan. So I was involved in that project from the very early days, did the first human studies.
I was very interested in the biology of migraine, always had been. I can't work out why I'd always been interested, most people who get into the area have suffered from the condition themselves and I don't. So I got interested by then being involved in the development of this treatment. As part of that, I needed to talk to the world experts at the time, guys like Peter Goadsby - though wasn't he wasn't famous then, he was still a registrar and in training! And I found that the migraine academic leadership were really very committed, passionate people with very good science behind them.
So I did that job, then I left The Wellcome Foundation and went to the UK, to Manchester, where I ran a business which was involved in doing clinical trials for the pharmaceutical industry. But because of my interest in migraine, I approached the professor of neurology and said “Are you interested in setting up a headache clinic?” and he said, “Funny, I just advertised for someone to set one up!” To cut a long story short, we set up what was the biggest dedicated headache clinic in the north of England and I was responsible for training the doctors.
And, of course, there was huge unmet medical need, there was disastrous care. I would talk to GPs and I was almost embarrassed to tell them the IHS (International Headache Society) criteria for migraine; one sided pulsatile headache… GPs would say “I've never seen this condition.” You’d think “what on earth were they telling their patients?” They were being told that that it was stress! It was really appalling. Here is a common condition that's easy to diagnose and had treatment. You think surely the doctors will be in on this and yet the general standard of care was extremely poor, and patients were massively grateful to talk to someone who recognised the condition, said “We know what this is, and we can do something about it.” People actually broke down in tears when we told them that.
Now I think you know from talking to migraine patients that Australia's standard of medical general practice is much better, but it's still a problem of patients finding someone who’ll listen to them and take their problem seriously. And it's highly treatable! That’s the thing, there are diseases like back pain and fibromyalgia that are hard to manage and so you think doctors are put off. Patients don't choose to have the disease they suffer from, they didn’t choose “oh, this is a doctor friendly one, this one is not.”
In the UK we started running quite a large clinic, I ran that until I left the UK and came back to Australia. And then I approached the pain clinic at the Royal Adelaide to ask if they were interested in setting up a headache service as they hadn't been able to see headache patients. As you know, patients otherwise had always gone to neurologists, but not all neurologists are interested, not all neurologists are very skilled, there was a huge delay in service delivery, so we set up a headache service within the pain clinic at the Royal Adelaide. I've now changed hospitals, because they moved, and I do a private practice.
So that was my clinical interest, but of course there was also the research side and as a professor of clinical pharmacology I was involved in research, I started looking at targeting immune and inflammatory pathways that might have been involved in migraine. We did some clinical trials, but my experimental therapies made people worse, not better, even though they hit the target. This is the nature of medical research, it’s not as easy as it sounds.
I've been involved in clinical research recently in a project which we think has some very exciting preliminary findings in doing blood tests to confirm migraine. It has been on hold due to a lack of further funding at the moment.
KS: Can you tell me a little bit about migraine pain, since you work with a pain clinic – do we know much about the mechanisms behind it?
PR: Not as much as we would like to. One thing that really surprises patients is you tell them the brain itself is incapable of detecting pain. Neurosurgeons know that you can operate on people's brains whilst they're awake. When you poke the brain you don't get pain, you get light or flashes or memories or so forth, so the brain itself is a pain insensitive organ but it's wrapped in structures that are exquisitely pain sensitive. And you can argue from a developmental point of view you've got these pain mechanisms to protect your most vital organ.
So we know that the pain of migraine must come from the membranes and the blood vessels because that's where the pain circuits are. But of course what's really going on in migraine has been difficult to elucidate. When I was in medical school I was taught the old vascular hypothesis that the aura was caused by vasoconstriction and pain caused by vasodilation. I didn't believe it at the time, because ischemia – lack of blood supply – doesn't cause aura, it causes loss of function, but at the time there was some experimental evidence in favour. We're now pretty clear that migraine is a disease of the brain, the cerebral cortex. We know that when people go into their migraine [attack], they often start with disturbances of mood or function, they may feel thirst, hunger, change in mood and so forth. This is clearly brain.
And then pain may start, throb and so forth, so we know that there's a secondary involvement of the membranes and the blood vessels. The most plausible hypothesis at the moment is that the abnormal brain activity causes a sterile inflammatory response on the surface of the brain and that's what causes the pain. And probably what distinguishes a migraine patient from a non-migraine patient is that a migraine patient, probably for genetic reasons, has a lower threshold for the brain to spontaneously go into this self-induced injury pattern.
And why does the brain do that? Well, I didn't design it, therefore I can't tell you why it does!
So we're quite good at the what, but the why and the how sometimes a bit different. To cut a long story short, we believe that the migraine pain has to come from the membranes and blood vessels around in the brain. And they are getting secondarily involved through a disturbance of brain function.
KS: I noticed you do research into biomarkers, can you talk a little about what that means for migraine?
PR: I've been wondering why patients with migraine get such poor support for medical reimbursement worldwide, this is not a uniquely Australian problem. There was a paper that came out about 2018 from several of the American and European luminaries. And it looked at what WHO data showing that, in working age adults in the developed world, so adults age under 50, migraine was the single leading cause of disability. But the interesting thing was the subtitle that said: “Now can we get the politicians to take notice?”
That's a cry for recognition, so these people have been in the whole area [of migraine research] for years, they've been at every public meeting, they've talked to every government authority. And they’re told it's not a problem.
I've had to work out why would the Federal Government not wish to pay $250 a month to give revolutionary treatment to some of our migraine patients, but they would be happy to pay $250 a month for rheumatoid arthritis patients for drugs which produce marginal benefit. And I've come to the conclusion it's the lack of the biomarkers. There's nothing objective. As you know, a migraine patient in between attacks can look fantastic, normal and great. And we may not see them lying in bed wanting to throw up, wishing the world would cave in on top of them.
But there's no measure for the suffering, and it's a poor thing that we don't believe people. People, almost all people, patients tell the truth, and they say, “I'm highly disabled by this condition.” They are telling you the truth. The problem is, but where's the evidence? Whereas with rheumatoid arthritis we've got all these inflammatory markers, we can measure the response. I think unfortunately the downside of 21st century medicine is we manage patients by numbers. We're taught that medicine is a science and it's not. It's an art based in science, with a scientific underpinning and the humanity got lost along the way.
With all these other diseases there's a number. We manage patients by numbers, and in migraine we don't have a number, we just have patients saying, “I feel terrible”. Do I need a biomarker to diagnose migraine? No. When a person tells me, “Since the age of 15 with my periods, I’ve got flashing lights, one sided pulsating headache, I felt sick, I was light sensitive, my mother has it too.” Do I need a blood test to confirm that diagnosis? Absolutely not.
I believe that it's hard to get resources for a condition where the only evidence is the patient’s report, and I think that's a cultural problem, a medical cultural problem which puts people at a disadvantage. And so, similar to patients with fibromyalgia, for example, or back pain, we haven't got any objective biomarkers. That's why I think the biomarkers can be useful.
The other problem, a real frustration we have, is we are unable to pick who benefits from many treatments. With the new anti-CGRPs, I've seen everything from 100% suppression of the condition, to “it made me worse,” and every shade in between.
So at the moment with all the preventative therapies, it's completely empirical, we just choose the drug with the least side effects and then move onto the others if they aren’t effective, and then to all the ones that there are barriers to give because of cost. The drug companies have trawled through their databases, all three have looked at the anti-CGRPs, is there anything that will tell us who's going to respond? Age, gender, duration of condition, nature of symptoms? They've turned the data inside-out, up and down and there's nothing, so we have to use the entirely empirical approach of “give it a go and see.”
Since the time I have been in medical practice, the treatment of cancer has been revolutionised. Now you take a biopsy, you do molecular profiling: “Oh, you've got a mutation in this single nucleotide polymorphism, you've got an overexpression of this pathway, we've got an inhibitor for you.” Molecular medicine.
And yet, in pain, in general, we are still using the same approach to treatment as the as the workers had who built the pyramids of ancient Egypt, who got a similar standard of medical care to what we get at the moment. It's just purely empirical and therefore it's unscientific, and if doctors are trained that you're going to work with scientific medicine, it's sort of unsatisfying using a purely empirical approach. What would be nice with biomarkers is if they would be able to tell us who will respond to what, that would be helpful. We don't have that as yet.
KS: Just a very small question to finish, what do you think is the future of migraine treatment and diagnosis?
PR: I think it's a very optimistic one. First of all we're getting closer to understanding the mechanisms, is there a single agreed mechanism which all the scientists agree is happening in migraine? No, but we're getting closer to working out what's going on. That's good.
I think, finally, migraine is being seen as a common cause of disability, which is highly treatable. I’ve had patients on some of the new anti-CGRPs who have gone off disability support to go back to work. I've had a student who was about to pull out of uni because she couldn't cope anymore, she's gone back and she's getting distinctions. Now, if I could offer a treatment for $230 a month that would take my back pain patients off DSP, the Federal Government be all over it. Why has it been so hard to persuade? Is it a women's health issue? I don't think so because the current health minister has put a lot of money behind endometriosis treatment and support. And he actually seems quite pro- women's health, there’s quite a lot of funding for women's health in the budget, and it was a total surprise that they funded Emgality.
KS: Well, we had been pushing quite hard for it.
PR: I know.
I think the future is we are now starting to get integrated molecular diagnosis. The anti-CGRPs are the first treatments ever to be developed specifically for the prevention of migraine; everything else was drugs used for other purposes.
The triptans around 1990 were the first treatments to be developed specifically for the acute treatment of migraine and now nearly three decades later, we have the first specific treatments [for prevention]. They will not be the last, because I've patients I give these drugs to that get no response. As more mechanisms are discovered, we'll get new treatments and I think what's exciting is that – remember this is a disease which is affecting homemakers, business people, chief executives, lawyers, airline pilots, the people that we want to be able to reliably perform, and the problem of the unpredictable disability is very difficult for patients to manage, so I think finally we're getting somewhere, and I think the future is getting much rosier.
And I just hope we see more of it really.