Ep. 177: Bridging Insights: Highlights from the EAN Pain and Headache Panels

00:00:00: Welcome to EANcast, your weekly source for education, research and updates from the European Academy of Neurology.

00:00:14: Hello and welcome to EANcast Weekly Neurology.

00:00:18: My name is Mesut Ashina.

00:00:20: I'm a professor of neurology at the University of Copenhagen and the director of the Center for Discoveries in Migraine.

00:00:29: These months, we are focusing on headache science, advances and key scientific developments of the year.

00:00:36: and pain science advances and key scientific developments also over the past year.

00:00:42: We will review new insights into pathophysiology prevention and treatment.

00:00:47: We will highlight their impact on clinical practice and to explore synergies between headache and pain research and thereby offering a concise overview of the year's key scientific advances.

00:01:02: And today I'm delighted to welcome my guests.

00:01:06: Dr.

00:01:06: Aksana Grosso, Head of the Research Unit and Clinician at the Diamond German Institute of Neurology and Neurosurgery, Headache Center in Kriysnau, Republic of Moldova, and Theodoros Mavridis, Consultant Neurologist at the Department of Neurology, Talat University Hospital in Dublin.

00:01:29: He has a special interest in headache science and cerebrovascular disorders.

00:01:35: Welcome, Maxano and Theo, and thank you for joining us today.

00:01:40: I'd like to start with the others, you know, and my question will be regarding the emerging preventive therapies.

00:01:50: We all know that we had a huge advances in migraine medicine by introduction of new anti-Siger-P pathway medications, but now we have something different.

00:02:02: It is about pituitary adenlight cyclics activating peptides.

00:02:07: And my question is that what makes the abbreviation of this peptide as a pack-up?

00:02:13: The pack-up as a compelling target, you know, which will be beyond the CRP prevention.

00:02:21: Thank you, Professor Asina for the kind words and I feel humbled to talk about backup which is, I may call it your baby and I really like talking about this new emerging target.

00:02:37: So as you know, backup is a neuropeptide that plays an important role in pain signaling, vascular regulation and neuroinflammation.

00:02:48: it is distributed across the nervous system and we know that has also its part and is concentrated in structure relevant to migraine, including the trigeminal ganglia and the dura mater and brain stem regions.

00:03:05: So basically if we take our knowledge from the cjrp we could say that is similar to cjrp and we know from studies also studies that you did that intravenous infusion of pack up can reliably induce migraine attacks in people with migraine but not in health individuals.

00:03:24: that means that we do have something there as a migraine specific biology.

00:03:30: so we know that pack up also.

00:03:32: has a different set of receptors as the CGRP does, like pack one, V pack one, and V pack two, and those can be upstreamed parallel to the CGRP.

00:03:44: So if I would say in a brief word, I would say that pack up is biologically relevant, and it's not something that will change our course from CRP to pack up but we can do them both.

00:04:01: So basically we will have more options in our arsenal with regards to the target on migraine biology.

00:04:10: Yes, and this brings me to the data that was published last year on the proof of concept study with the anti-pack-up monoclonal antibody.

00:04:23: Can you briefly tell us about the study design and the major outcomes of this study, please?

00:04:30: Great, great.

00:04:32: You're talking, of course, about the Hope to Trial, which is a phase two trial.

00:04:36: Again, I would tell all our listeners to go to our previous podcast, which was a really interesting podcast about this trial.

00:04:45: I won't go into much details, but I will tell you that this was a phase two trial.

00:04:50: It was very encouraging.

00:04:52: And basically, we had patients who got the L-U-A-G-Y-Zero-Nine-Triple-Two, which was the agent, anti-pack-up monoclonal antibody, in a lower, higher dose, or placebo.

00:05:09: It was a phase two trial.

00:05:11: And the interesting thing about this trial, it was the outcome.

00:05:16: So usually in the phase two trials, our trials that we are focused on adverse events, mostly and we don't go for bigger results like clinical significance or reduction on mean migraine days.

00:05:28: This is something that you have to be a bit bold to do.

00:05:32: that because those trials are usually neutral not only due to their design but the small number of patients that we usually recruit on those phase two trials.

00:05:43: But this was very surprising that they hired also a meaningful reduction in monthly migraine days compared to placebo.

00:05:50: What can we say about what stands out from this trial is that we had also patients who have also tried multiple preventive treatments.

00:05:58: And this shows us the concept of pack-up inhibition could be a valuable addition to our already treatment arsenal.

00:06:08: So I wouldn't say that it will replace the CGRP-moclonal antibodies anytime soon, but it could be a complement or alternative in the future.

00:06:17: We know I can speak later on about biological markets that we can input further in our headache practice.

00:06:26: Yeah, it's great data in a way that it actually opens up for the possibility that we can actually target another alternative peptide, which is completely different from the CGRP in terms of the different family, but also different receptors affinity.

00:06:46: but as you mentioned that these kind of trials were relatively small sample size and that's why we need to wait for the phase three, phase two B and phase three trials.

00:06:58: Another interesting question is the clinical practice.

00:07:01: we usually hear from our colleagues.

00:07:03: You know, we have quite a big, you know, large arsenal of the acute medications.

00:07:08: You know, people usually start with the simple analgetics, or NSAIDs, and then the tryptons.

00:07:15: And now we also have G-pads.

00:07:17: And the G-pads acute medications acting on, you know, as the antagonists of C-JRP receptors.

00:07:24: We also have a one-dieton, which is a lasmidetone acting on serotonin-V-H-T, one-F receptor, which is different from the tryptons.

00:07:35: With all these arsenal and the absence of the good head-to-head trials, How can we navigate in the clinical world and can start kind of ranking the medications in terms of efficacy, durability and safety?

00:07:54: Okay, very, very interesting question and I will refer our audience to the yearbook of this year, specifically the headache part that we write some data about this recent network meta-analysis that your group did regarding the efficacy and safety of the acute medication.

00:08:15: I will explain to the audience basically what network meta-analysis is in a brief sentence.

00:08:22: Basically, we take all the trials that have compared everything against another medication or placebo.

00:08:29: And then we try from A to B and then from B to C to do the comparison of A to C. So it needs also a really good Bayesian model.

00:08:38: It's very, very difficult to do.

00:08:41: Also, it has its limitations.

00:08:43: But As you mentioned before, we have a lot of data comparing one drug to the other.

00:08:48: So the robustness and the data that we can get from those network mental analysis are really, really strong.

00:08:59: And basically, in a sentence, what it says are symptoms are and will stay for a long time.

00:09:06: The best and most efficacious medication that we have in acute migraine treatment.

00:09:11: And that is a fact.

00:09:13: Whoever wants to contradict that, he can read all the data that he wants, but still triptans hold their ground.

00:09:20: Also in your clinical practice, do you think that it is surprising for you that the triptans are so efficacious?

00:09:27: No, it's not surprising, but I would say that it could be... Because I see that for most other physicians and I see different levels of starting the treatments.

00:09:38: I would say that it could be and I use it perfectly as a first line treatment.

00:09:44: I don't wait for the NSAIDs to work.

00:09:46: So basically the net analysis actually outperformed also newer options like G-pants and D-tons in terms of efficacy for most patients.

00:09:56: So the most efficacious of them all stand out to be summa triptan which was the reference with no, not better than zolmitriptan or risa triptan in terms of statistical significance, but L-triptan was even better than them.

00:10:12: So I would say that it is very important for physicians to know and to use triptons as a first-line medication.

00:10:21: This is what I do and I know that some countries don't have all the triptons or all the formulation or of course it's also about the money and the reimbursement from the state.

00:10:32: So basically, you know, these kind of studies are important as you mentioned because they can reshape, you know, our therapeutic landscape in a way that we can guide actually the guidelines.

00:10:43: you know, in terms of the ranking medications and as you said that the four triptons stand out as the best, we don't need to try all the triptons, but we need to try four of these, you know, whatever is available, there is access for these triptons, it's important.

00:11:01: Another important message to the authorities is I think it's important that we need to expand that our essential list of the WHO's, you know, the list of medications, not only Sumo triptan, but also include other triptans because patients deserve, you know, effective treatment.

00:11:19: So I think that it is important and as you mentioned that this kind of status is the only way we can actually address the issue of the head-to-head trials.

00:11:29: This brings me also to another important topic about the biomarkers.

00:11:37: And in this context also some of the status... on pathophysiological aspects.

00:11:45: You know, we had a major publication, you know about this publication in science, and the question is to you, can you elaborate a little bit about this discovery that the cerebrospinal fluid solutes, you know, they can in fact activate trigeminal ganglion neurons, and they can in a way that explain, you know, the link between aura and headache, you know, and Could this mechanism be a novel avenue in your opinion or you have some critical view on that?

00:12:17: Yes, this study was very, very interesting.

00:12:20: Again, it's a basic science study, meaning that we are dealing with mice and lab rats.

00:12:28: So basically, this study provided a mechanical bridge between aura and the headache.

00:12:35: As you know, of course, we have many debates over this about the migraine without aura or the pure aura migraners that are completely different population.

00:12:46: And we can keep talking about that for ages.

00:12:48: But in terms of this specific study, we would say that the researchers found that after cortical spreading depression, the CSF composition changes and they took that

00:13:00: post

00:13:01: aura let's say post cortical spreading depression which mimics the migraine aura and they applied it to trigeminal neurons and that activated them directly.

00:13:14: They did that with a normal CSF and that did not.

00:13:17: So basically it shows that the solutes, the different status and composition of the CSF after the cortical spreading depression, like the changes in the potassium, the glutamate, of course, which is an excitatory substance and the lower pH, so that it does activate other parts of the brain.

00:13:39: It's not basically a simple visual phenomenon followed by pain, so they're interconnected.

00:13:45: And this comes to the previous thing that we were saying that sometimes some people get an aura and sometimes people get an aura with a full blown headache, which is not really required to have a full blown migraines headache in the ICST-III criteria.

00:14:00: But this means that after an amount of threshold, the CSF solutes that changes can make the migraine happen, can bring up the migraine, can alter the threshold.

00:14:14: So, basically, suggest a chemical cascade that is linking the cortical spreading depression to peripheral nociception because it can activate trigeminal neurons.

00:14:24: It's very, very important to sense that idea and to link that, that migraine aura and migraine and the pain itself are not completely different episodes and one can bring the other.

00:14:36: It's not just that interconnecting in terms of phases.

00:14:40: Yeah, I mean, in fact, it's a fascinating findings, you know, and with all reservations, of course, it's a preclinical finding that, you know, you can explain the link between the cortical spreading depolarization and activation of the sensory afference, explaining the head pain.

00:14:58: So this interface is very, very important.

00:15:01: And also it brings us to this hypothesis of top-down hypothesis, when it starts in the brain and then goes and activates the peripheral mechanism.

00:15:10: But some of the studies, in fact, that we published also, I just can tell you, Theo, is that in humans show that you can actually activate the trigeminal vascular system and then induce aura symptoms, which is a completely different view of the down top, the hypothesis that basically it kind of make a distortion of this sequence that we used to as a clinician, first aura and then head pain.

00:15:39: And in this case, it is first head pain and then the aura attack.

00:15:43: So the issue is quite complicated.

00:15:45: Do you agree, Theo?

00:15:47: Yes, I do agree.

00:15:48: And this is the fact that we also see from our patients in clinical practice.

00:15:52: It's not like what they're written in the book.

00:15:54: So first the aura, then the aura stops and then you have the headache.

00:15:58: Sometimes they overlap not only.

00:16:01: after a few minutes, but sometimes the headache can be there before the aura starts.

00:16:06: And some people or physicians also can be confused by that and say that's this photosensitivity.

00:16:13: No, it may not be photosensitivity because if you dig into that, you can see aura symptoms, visual aura symptoms that are happening after the headache started, something that we see in clinical practice, but the books have always put it in a sequence.

00:16:27: It's not exactly black and white.

00:16:30: I agree.

00:16:31: Thank you.

00:16:31: Fascinating topic.

00:16:33: Now to you, Aksana.

00:16:34: We're talking about the advances in mechanisms and diagnosis and was a focus on neuropathic pain.

00:16:40: This is something also fascinated me for many years.

00:16:42: You know, it's quite complex.

00:16:44: You know, I would say that we have not been so successful in terms of the new treatments.

00:16:50: And one of the things that it's important that to understand the mechanism.

00:16:55: And can you tell us a little bit about the most important recent discoveries in neuropathic pain mechanisms and also how the new diagnostic tools improved our ability to identify and treat neuropathic pain?

00:17:12: Hi, everyone.

00:17:13: Hi to the followers and hello to Professor Shina and Teodoris.

00:17:18: And thank you for the YAN headache panel to inviting YAN pain panel to such a collegial discussion.

00:17:27: And I would like to say that this year YAN pain panel decided to highlight a very important theme from our point of view, a chronic pain.

00:17:41: And you can look in the young yearbook and you will see that we put there information about the management of chronic pain associated with temperamental disorders, information about chronic visceral pain, chronic pain in pediatric patients, chronic post-surgery pain, and of course new tools like virtual reality training in chronic back pain.

00:18:10: to highlight this theme because we consider that in our field was a major shift that chronic pain is no longer seen simply as a symptom, but as a complex health condition that require biological, psychological and social support.

00:18:29: And to return to your question about the important discoveries in neuropathic pain mechanism.

00:18:36: I would like to mention a review done by Golmakani and colleagues, and their work highlights that macroRNAs are key regulators in neuropathic pain.

00:18:50: I think this is important because these small molecules can amplify or dampen neuroinflammation, nerve accessibility, and even the nerve repair.

00:19:03: In the same review, the authors presented an interesting aspect like exosomal macroRNAs that are the same small molecules that can travel between self and communicate.

00:19:19: And these macroRNAs can carry signals that will increase the pain or even help reduce it.

00:19:26: And this interesting discovery will shift the field from the symptom targeted approaches to the biomarker guided diagnostic and even targeted RNA therapies that will help us to move to the precision medicine and to the treatment that are driven from the mechanism, not just from the symptom.

00:19:54: And of course, this discovery gives us new interesting diagnostic tools that will help us to transform all the fields of the... chronic pain, not only the neuropathic pain, and these tools like skin biopsy, quantitative sensory testing will help us to detect small fibro nerve damage much earlier and much accurately.

00:20:25: At the same time, there are a lot of advanced imaging technique, electrophysiological studies and these biomarkers like inflammatory and macro RNA signatures that will give us a deeper insight into the mechanism behind the chronic pain.

00:20:45: I think this is a very interesting discoveries that will help us to personalize the treatment and will replace the traditional trial and error approaches that we used to do since centuries.

00:21:04: Yeah, and this brings me also, you know, with all these advances in mechanisms and diagnostics that you mentioned about the biomarkers.

00:21:11: What about the management strategies?

00:21:14: This latest evidence that you tell us about what is the role of pharmacological and non-pharmacological treatment in management.

00:21:22: And if you also share with us your view on interventions which show the strongest long-term benefit for patients, please.

00:21:32: Recent evidence in chronic pain management shows that pharmacological and non-pharmacological treatments are not alternative.

00:21:40: They are not parallel.

00:21:41: They are complementary pillars.

00:21:43: And of course, the medication remains essential, especially when the pain is not susceptible or neuropathic, dominant, but they don't work very well alone.

00:21:59: they should be paired with active approaches like exercise, rehabilitation, cognitive mindfulness, therapies, neuromodulation, or even education and lifestyle intervention.

00:22:10: And all these combinations will promote neuroplasticity, function and long-term recovery.

00:22:18: It's not just about to stop the pain, it's to change the system.

00:22:26: So this... modern approaches of so-called integrative and mechanism-based management help us understand that the pharmacotherapy target the biological drivers of the pain.

00:22:43: And the non-pharmacological therapy target the other part of the biopsychosocial approach to the chronic pain.

00:22:53: So the medication are on biological and non-pharmacological therapy on the psychosocial aspect of the pain.

00:23:02: Which one of the interventions showed the longest benefit?

00:23:10: In the pain field, there is a term called multimodal care that combines biological, psychological and functional intervention.

00:23:26: It's the best suited and show the very good results with the improvement of pain, function and quality of life.

00:23:39: see that the medication are very helpful when they enable patients to participate in acute rehabilitation, not when taking in isolation.

00:23:51: So the improved sustained and long-term improvement will be driven by neuroplasticity, relaysion, functional restoration, not just simply symptom suppression.

00:24:05: Well, fascinating topic and also just, you know, illustrates again how important is that we have, we try to have a personalized approaches, but also on the same hand, we also have a pretty standard multi-disciplinary care pathway for the patients.

00:24:23: so we can implement across many countries, I hope, so that everybody can get the same quality of treatment because those patients really need a good treatment to improve the quality of life.

00:24:36: This brings me also to another interesting topic about the translational research.

00:24:40: Can you tell us about the recent translational research findings which showed some of the greatest promise for clinical applications and how this could affect to bridging the gap between what we know about the mechanisms and everyday treatment?

00:24:59: I will try to answer but I would like to mention that not in all countries we have a very good multidisciplinary pathway developed and in the western European country there is a long standing tradition about this.

00:25:16: but in Eastern Europe and the other part of the country is just people just are hearing about it and they are trying to apply it.

00:25:25: and about the question what is the recent translation of funding, I think from the clinical point of view the most interesting will be this digital pain phenotyping.

00:25:38: So this that will help us to stratify the patient.

00:25:44: What is when we speak about personalized care we think about not just a pain, a mechanism of pain that patient is presented, but the other part of the problem, like multidimensional experience of the patient.

00:26:04: And when we try to apply this in clinical practice, it means that we have to move from what works generally for pain patients to what works best for this person.

00:26:20: at this stage with this mechanism of pain.

00:26:24: So I think this is the most important to be translated into the clinical practice and it will be more like translational findings.

00:26:37: I don't know if we are very close to this translation, but I think we are on the way to do it, especially from the publication that are coming from the western part of Europe.

00:26:53: There are more translational research and implementation.

00:26:59: Unfortunately, from my part of the world, it's a bit less.

00:27:04: Okay.

00:27:06: Since we have this joint panel discussion, headache and pain, head pain and pain, let's say cephalic and non-cephalic pain.

00:27:18: That will be probably the most correct way to illustrate some of the differences in terms of localization.

00:27:26: But what about the mechanism?

00:27:27: For many years, we've heard about the shared mechanisms between the sephalic and non-sephalic pain.

00:27:36: There are some differences, but let's talk about some shared mechanisms and challenges.

00:27:42: Theo, what do you think about that?

00:27:44: Yes, what about the shared mechanisms?

00:27:46: I would say that the most important thing and... I will go first to the central sensitization the comorbidities that are mostly mentioned in both diseases and we know in headache in particular migraine.

00:28:01: central sensitization drives both symptom burden and progression and this is similar to chronic pain syndromes and we need to identify this earlier.

00:28:13: And we learned from pain clinical trials that we need to address also other disorders, not only the headache and the pain, the migraine itself, but also spring for mood disorders, sleep dysfunction, and as Oxana said, multidisciplinary multimodal care.

00:28:31: We see that a lot in clinical trials that are addressing either chronic migraine or refractory or resistant migraine or difficult to treat.

00:28:40: And recently we published a paper regarding the steps dealing with refractory headache, refractory migraine.

00:28:48: And most of the steps need to address are telling us to address also the comorbidities, address also things that are already known to the pain physicians.

00:29:01: Yeah, you're absolutely right.

00:29:03: And another question is also very important that we have progress in research, you know, both in the headache field but also in the pain field.

00:29:14: And the question is to Oksana, what can headache research, you know, that we had so many good things happening in our field and discoveries teach us about pain medicine.

00:29:26: whether there any kind of things that you think that from the headache field could be tried or to explore in pain field also.

00:29:37: Yes, there are a lot of overlap and as we know the headache field is coming with a very precise research with very important molecular insights and especially in the migraine field with the new targets and I think this could be extrapolated to the pain field.

00:30:00: in the same way the pain field.

00:30:03: will come to the headache field and give this overview of multidisciplinary care of the chronic pain patients as a whole when we are just targeting not a mechanism, a molecule or treatment options, but we look at him in a holistic way.

00:30:27: I think it should be explored here.

00:30:31: I think it's so important what you say, because I remember that when I started in headache research and headache science, I really added deep dive into all the discoveries in pain field.

00:30:44: They were so important to understand the headache mechanisms.

00:30:50: To understand the headache mechanisms without knowing the pain field, I would say it's almost impossible.

00:30:56: So major discoveries in pain field really shaped my understanding also about the head pain, the possible mechanisms.

00:31:05: So extremely important that we have these mutual insights, we kind of interact, we understand each other.

00:31:12: And looking forward for the opportunities ahead, Theo, what do you think about the opportunities of the joint research in pain and headache?

00:31:20: This is a very, very important subject.

00:31:22: for years.

00:31:24: Those two groups were worked, unfortunately, not with each other, but separate.

00:31:30: I think the collaborative work... would first suggest on doing research on biomarkers of sensitization.

00:31:37: We have seen some with the saliva CGRP but we see that also in the pain science as well nowadays.

00:31:44: So we could work closely first of all on the biomarkers and then some things that the pain physicians are more.

00:31:54: they have more knowledge on which is the third digital endpoint with using wearables or diary based platforms that we.

00:32:02: mostly use.

00:32:04: If we manage to do also better clinical phenotyping and make sure that we have consistency in our clinical trials and in our patients, then we could improve the consistency of our guidelines, not only the headache guidelines, but also the pain guidelines.

00:32:22: And we know that there are some differences if you go to the pain guidelines in terms of what they say.

00:32:30: what this is.

00:32:31: are what all the diseases are labeled compared to the ICST-III.

00:32:37: I think we should have a common goal towards that and it's very interesting to ultimately improve access to mechanism-based therapies globally and not just throwing medication to a patient.

00:32:52: Well, very, very good.

00:32:53: Thank you, Theo.

00:32:54: So this brings me just to say a couple of words before we stop that all these emerging therapies, regardless of coming in the headache field, on the pain field, They come because of science.

00:33:10: So we need to support good science in both disciplines, in both fields, because this really brings a difference.

00:33:17: So bringing discoveries into lives, you know, this is very important.

00:33:22: And we are absolutely, I mean, common in this goal.

00:33:27: And this is very important because it will have a clinical impact.

00:33:31: So we need to understand more about the mechanisms and also a good thing also to interact.

00:33:37: between the two fields, because we can learn from each other a lot of things.

00:33:42: And I think that this podcast illustrates many commonalities, not only the differences, but also the differences which can bring us to understand each other's fields much, much better.

00:33:54: So thank you so much, Oxana.

00:33:56: Thank you so much, Theodorus, for this fascinating conversation.

00:34:00: And thank you, listeners.

00:34:02: So I hope that you enjoy our podcast.

00:34:04: Thank you.

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