Peter J. Goadsby | Dean of Biomedical Sciences; Senior Affiliate to the President, King Abdullah College of Science and Expertise, Saudi Arabia; Professor Emeritus, College of California Los Angeles, USA; Honorary Marketing consultant Neurologist, King’s Faculty Hospital and Nice Ormond Road Hospital, London, UK
Quotation: EMJ Int Cardiol. 2026; https://doi.org/10.33590/emjintcardiol/479T91H3
Whenever you started your work, the vascular principle of migraine was nonetheless dominant. What particular observations most clearly satisfied you that vascular change was epiphenomenal fairly than causal?
After I first heard folks discuss migraine, there have been two issues that struck me as odd concerning the vascular principle. The primary was that, on the time, there was an idea that migraine was attributable to some type of circulating serotonin-releasing issue producing vasodilation. That struck me as an odd factor to counsel as a result of something that circulated would go to each side of the pinnacle, whereas migraine is predominantly one-sided, in order that didn’t make any sense to me.
The opposite factor was that, on the time, James W. Lance’s group on the College of New South Wales, Australia, was within the signs that happen earlier than ache, the so-called premonitory signs, resembling focus impairment and fatigue. It was merely unattainable for me to consider blood vessels inflicting folks to be fatigued. Perhaps that was simply because I didn’t know sufficient on the time, but it surely didn’t appear to make any sense to me.
So, as a result of the prevailing explanations didn’t make sense, it made me assume that there was prone to be a neural clarification, a central nervous system clarification, as an alternative.
Your work led to the invention that migraine includes the discharge of the neuropeptide calcitonin gene-related peptide (CGRP) from trigeminal sensory nerves, and finally the event of gepants, CGRP receptor antagonists. The success of gepants is extraordinary, however many sufferers both partially reply or don’t reply in any respect. What does non-response train us about migraine heterogeneity?
CGRP pathway blockers are available two kinds. There are gepants, and there are additionally the CGRP monoclonal antibodies that bind both to CGRP itself or to the receptor. The work that I did figuring out CGRP was performed with Lars Edvinsson at Lund College, Sweden. Solely about half of migraine victims who’re handled could have a helpful response, and about 40% could have a spectacular response. So, what that tells you is that there are different facets of the pathway, different transmitters, that have to be concerned. That’s irritating for the individuals who don’t reply, after all, however I see it as a chance. To me, it says there’s extra to do, and, invariably, the researchers’ clarion name is that extra analysis is required.
Some of the fascinating facets of gepants is their twin acute and preventive position. What does that duality reveal about migraine pathophysiology?
First, it establishes that the notion that there’s a strict demarcation between preventive remedies and acute remedies have to be flawed. When you have a look at the literature, it’s not the primary instance of this, but it surely’s definitely the clearest instance.
Preventive medicine, usually talking, will not be absorbed in a short time. When you take medicine like topiramate or propranolol, they’re absorbed comparatively slowly, in order that they’re impractical merely from a pharmacokinetic viewpoint. You may’t get them on board quick sufficient. After which, there are sudden penalties. Triptans are nice acute remedies, and they might in all probability be good as preventives, aside from the blood vessel constriction facet. In a proportion of individuals, they improve blood strain, and their means to induce complications, so-called remedy overuse headache, which isn’t common however occurs in a considerable proportion of sufferers, implies that taking them day by day carries so many draw back dangers that you simply wouldn’t consider using them as preventive remedies.
The overarching level for me is that should you assault the suitable mechanism, or block the suitable mechanism, then it actually turns into a query of pharmacokinetics, absorption, and unwanted effects as as to whether you’ll have the ability to use the drugs in each an acute and a preventive trend. I think that’s going to be the overall rule as we get extra particular medicine, that you simply’ll have the ability to develop medicine that may do both.
A extremely good instance is eptinezumab, a monoclonal antibody given intravenously that works fairly effectively acutely. Its intravenous administration is as efficient as a gepant given orally. In order that’s a clear-cut instance of a preventive remedy working acutely. Then, after all, you could have all of the gepant information for a category that began as acute remedies and likewise works preventively.
I feel the opposite vital factor is that it makes early medication growth lots simpler, since you now not have to consider fashions and methods by way of whether or not they’re preventive or acute; it’s merely not a related idea. What you’re making an attempt to do preclinically within the laboratory is perceive the drivers within the biology after which goal them. When you provide you with a drugs that has a protracted half-life, and there are extra individuals who want it as a preventive medication, then you could go down that street. When you provide you with a drugs that’s extremely shortly absorbed and has a brief half-life, then you could go down the acute remedy street. At that time, growth begins to be pushed by these issues and never by the mechanism itself. Europeans will probably be acquainted with flunarizine, which they have an inclination to consider purely as a preventive medication, however there’s really a randomised, placebo-controlled trial displaying that it may be an efficient acute remedy when given intravenously. Now, nobody actually does that; it was by no means developed that approach, and it’s not particularly sensible intravenously, but it surely does present you that the precept is there, and that the underlying precept might be appropriate.
CGRP-targeted therapies symbolize one of many clearest examples of translational neuroscience succeeding in medication. Do you are worried that more and more restrictive remedy pathways danger delaying biologically acceptable remedy till migraine has already turn out to be entrenched?
In a super world, you’d give each individual in entrance of you the remedy that’s ultimate for them. However we don’t really know what’s ultimate for everybody sitting in entrance of us. Are there individuals who can be higher off getting onto these newer medicines earlier? Positive. Is that sensible from a price viewpoint? No.
Do I have a look at the lengthy sport? Sure. If I have a look at the gepant tablets, they’ll finally come off patent, and somebody will make an inexpensive generic model. Triptans had been like that 25 years in the past. Again then, medical doctors would inform sufferers that triptans had been costly, whereas now nobody says that anymore as a result of they’ve all gone generic.
So, within the brief time period, sure, value restrictions are a draw back, however within the medium time period, I settle for the implications of medicines being costly initially, as a result of I feel it facilitates the event course of. Finally, with tablets, you permit one thing behind. Take a look at propranolol; there was a time when propranolol was costly. Now, it’s generic, low-cost as pennies and broadly helpful.
The truth that the WHO now lists sumatriptan as an important medication for each nation as a result of it’s turn out to be low-cost sufficient is exceptional. When you’d mentioned one thing like that 30 years in the past, folks wouldn’t have believed, “These medicines are too costly,” and so forth. Thirty years later, the cash that was sloshing round, so to talk, has left a legacy: an inexpensive, efficient medication resembling sumatriptan that WHO believes the creating world ought to have the ability to use. That basically is a legacy, one era leaving one thing behind for the following.
I feel the identical factor will occur with gepants and the pill medicines that comply with. So sure, presently it’s a draw back, however in the long term, if we hold creating new medicines, you solely need to provide you with one thing actually spectacular for 1 / 4 of individuals each 20 years. In 100 years, you’ve kind of bought the issue found out. That’s really not too dangerous.
Within the historical past of humanity, migraine is a really outdated downside; descriptions return to round 4,000 BC. So, to assume that we’d get most of it sorted inside 100 years is fairly good going.
Simply out of curiosity, how do we all know migraine was being described in 2,000 BC?
There are hieroglyphic depictions of individuals holding or making use of issues to their heads, which some folks interpret as representations of headache issues. Extra curiously, there are translations of medical writings from Mesopotamia relationship again 3000 years.
Whenever you learn these texts, you may clearly see themes that resemble migraine. If somebody is described as having ache or discomfort within the head, avoiding gentle, and vomiting, notably if the affected person is a girl, there’s a great likelihood they’re describing migraine.
Students who examine these historic languages have pulled collectively these descriptions and printed them in collections and books, and while you undergo them, you may recognise medical patterns which can be remarkably acquainted at present.
Aura stays some of the neurologically intriguing phenomena in medication. What facet of aura physiology do you assume continues to be most poorly understood?
I feel the way it begins continues to be poorly understood. I can set off an aura within the laboratory by poking a needle into the mind throughout recordings, however clearly that’s not what’s occurring in folks in real-world conditions. So how does it occur de novo?
To know the start of one thing is to grasp cease it. We perceive quite a bit concerning the course of itself, however I don’t assume we but perceive what triggers it on the very outset, and that appears to me essential if we’re going to grasp stop it.
Do you could have any theories?
I feel the predisposition is there on a regular basis, but it surely’s usually being suppressed, and the suppression methods are biking up and down. I think it’s multiple suppression system.
Let’s say you could have the inherited tendency. The rationale I say that’s as a result of we’ve seen, with purposeful imaging, you can set off an assault of migraine experimentally. When you have a look at folks with the inherited tendency who’re triggered right into a migraine with out aura, after which particularly have a look at those that have a historical past of aura, they don’t essentially develop aura throughout the experiment. However should you have a look at the blood movement in that group after giving them, say, a nitroglycerin set off, you may detect decreased occipital cortex blood movement. It’s not at a degree that’s producing signs, however you may measure it.
I feel there’s a organic signature there on a regular basis. They all the time have the biology, or not less than the predisposition, after which one thing pushes the system previous a threshold that kicks the method off. I think that threshold is managed by a number of methods within the mind, as a result of most issues within the mind have redundancy constructed into them.
My guess is that there are a number of biking regulatory indicators, maybe 5 completely different methods, and so they all have to achieve their nadir at roughly the identical time. That alignment could take time, and it’s in all probability influenced by different circumstances as effectively. So, I feel it’s a mix of getting the predisposition after which creating synchronous dysfunction within the methods that usually hold the biology in verify.
Now, whether or not that synchronisation is random or whether or not one thing actively causes it, I don’t know. In the mean time, it’s basically an untestable speculation.
Do you assume migraine with aura and migraine with out aura are essentially the identical dysfunction expressed in another way, or biologically distinct entities that we proceed to group collectively for medical comfort?
I feel it depends upon how excessive up you wish to have a look at it from. You understand, everybody on Earth appears the identical should you’re far sufficient away. After I have a look at migraine with and with out aura, it nonetheless strikes me as migraine. I feel aura is a selected physiology that may be concerned in migraine, however I’m undecided that aura is quintessentially what migraine is about. I in all probability have a barely disruptive view about that.
I feel migraine is essentially a dysfunction of sensory modulation, an issue with controlling incoming info, a heightened sensitivity to sensory enter: photophobia, allodynia, vertigo, and so forth. Aura appears a bit of separate from that course of as a result of, as we presently perceive it, one of the best mannequin for aura is cortical spreading despair, or cortical spreading depolarisation, and that’s not essentially a sensory dysmodulatory course of, though the disinhibitory facets would additionally clarify aura.
So, are they essentially the identical? I feel folks with migraines in all probability do share the identical underlying downside. I don’t assume the biology of aura itself is essentially the identical, though its facilitation could also be. Each appear to contain a failure to correctly include irregular exercise, if I can put it that approach.
The nervous system actually likes to maintain issues in verify. The physique is like that usually, all physiology is. In case your coronary heart price goes up due to sympathetic activation, the vagus nerve tries to convey it again down once more. That’s homeostasis. The drive towards homeostasis could be very sturdy and really effectively developed in people.
I think that, at its core, migraine includes dysfunction of methods that will in any other case keep homeostatic management. That’s the elemental factor that migraine with aura and migraine with out aura share. So, within the larger image, I’d positively be extra of a lumper than a splitter relating to migraine with aura versus migraine with out aura.
Definitely, from a preventive standpoint, each kinds appear to answer the identical preventive remedies. I don’t assume we’ve actually answered whether or not that’s equally true for acute remedies. We definitely haven’t addressed it absolutely with the gepants as a result of we don’t but have an injectable formulation to check that query correctly. The jury continues to be a bit of bit on the market, however, general, my reply can be sure.
Analysis has proven that frequent use of codeine-containing medicines for migraine can contribute to medication-overuse headache and dependence danger. Why do opioid-containing brokers resembling codeine stay so entrenched in migraine care regardless of the proof towards them?
The dependence danger is essentially an opioid concern. Whether or not you could have migraine or not, should you repeatedly expose somebody to opioids, there’s a danger of dependence. Treatment-overuse headache is a distinct and extra attention-grabbing phenomenon, as a result of it may be produced by triptans, which don’t have abuse or dependence potential, and it may also be produced by opioids like codeine, which do have dependence potential. So, I don’t assume dependence itself is the important thing concern in medication-overuse headache as a result of they’re really fairly distinct phenomena.
One of many issues the medicines related to medication-overuse headache have in frequent is that their receptors are present in brainstem sensory-modulating areas. For instance, within the periaqueductal grey you’ll discover each triptan receptors and opioid receptors. One other frequent characteristic is that these medicines are all agonists; they activate the receptor. So, you may think about repeated activation frequently driving these methods. Against this, antagonists such because the CGRP blockers stop activation however don’t themselves flip the receptor on. When you repeatedly activate a system, you’re going to induce downstream adjustments in second messenger pathways and broader community operate. I feel that, at some degree, might be the organic foundation of what’s happening.
So why do opioids stay entrenched in migraine care? Partly as a result of they’re outdated, acquainted medicine that individuals are used to utilizing for ache. When you assume migraine is essentially only a head ache downside, then the logic turns into: first use paracetamol, then a non-steroidal anti-inflammatory, and, if that doesn’t work, scale as much as codeine. There’s a familiarity issue, but additionally an inclination to lump migraine along with different ache circumstances, which I feel is a mistake as a result of migraine is definitely far more than simply ache. Then, there’s the protection. Folks actually don’t die taking 30 or 60 mgs of codeine, and also you don’t essentially want a complicated prognosis to prescribe it; you may merely say “head ache.”
Lastly, what are a very powerful translational gaps that stay in migraine medication at present, and which of your present analysis instructions are geared toward closing them?
One of many issues we’re fairly focused on in the meanwhile is knowing vertigo in migraine, and notably this situation referred to as vestibular migraine, the place vertigo is a distinguished element. We wish to perceive why about half the folks we see have some extent of vertigo related to their assaults.
Fairly often, vertigo shouldn’t be the primary characteristic, however for folks with vestibular migraine, it’s a extremely huge deal. In the identical approach, for some folks with migraine, gentle sensitivity is a giant deal, and so they come to the clinic sporting sun shades. However for others, gentle shouldn’t be such a serious concern. We don’t actually perceive why.
In the mean time, we’re notably focused on understanding how vertigo and migraine match collectively, how they have an effect on one another, and the way greatest to deal with that facet of the dysfunction. Little or no systematic work has been carried out to take a look at that physiology, and that’s one of many translational gaps we’re making an attempt to deal with.
