Next Gen in 10: Mapping Pain Sensitivity in Endometriosis

In this episode of the GOSH Podcast’s Next Gen in 10 series, we are joined by Alison Luo, a Master’s student at the University of British Columbia supervised by Dr. Paul Yong. Alison discusses her research on pain sensitivity and central sensitization in endometriosis using clinical mechanical testing, as well as her work validating a prediction model for pain-related quality of life outcomes after endometriosis surgery. Together, we explore how better understanding pain processing may help inform more personalized approaches to endometriosis care.

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Transcript

00:00:02 Intro 

Thanks for listening to the GOSH Podcast, the Gynecologic Oncology Sharing Hub. We share real, evidence-based discussions on gynecologic cancers featuring stories from patients, survivors, researchers, and clinicians. Our podcast is produced and recorded on traditional unceded territories of the Musqueam, Squamish, and Tsleil-Waututh Nations. It is produced by the Gynecologic Cancer Initiative, a BC-wide effort to advance research and care for gynecologic cancers. 

00:00:36 Sabrina 

Hi everyone. My name is Sabrina and I would like to welcome you back to our new segment on the GOSH podcast called Next Gen in 10, where we feature GCI trainee research. Today we are joined by Allison Liu, who is a master's student at the University of British Columbia in the Women and Children's Health Sciences Program. Supervised by Dr. Paul Young, her thesis focuses on measuring hypersensitivity and widespread pain through clinical mechanical testing to better understand normal pain processing and central sensitization. She is also working on validating a clinical prediction model for pain-related quality of life outcomes after endometriosis surgery. So, Alison, welcome to the GOSH Podcast. 

00:01:22 Alison 

Thank you so much for having me. 

00:01:24 Sabrina 

Fantastic. We're so glad to have you here today. Can you start by just telling us a bit about the background on your research topic as well as the gap that your research is really aiming to fill? 

00:01:36 Alison 

Yeah, so I work at the Endometriosis and Pelvic Pain Lab at the BC Women's Hospital and Health Center. And my research focuses on looking at endometriosis-related pain and pain outcomes after endometriosis surgery. So specifically the role of central sensitization, which is like widespread pain and hypersensitivity. And like you said, validating a prediction model for pain related to quality of life after surgery. So I'll kind of start with a background on endometriosis. Endometriosis is a chronic inflammatory condition that affects about one in 10 women of reproductive age and an unknown number of gender diverse individuals. And it's basically where tissue similar to the lining of the uterus grows outside of it. It's hormone dependent, linked to significant physical, emotional, and psychological burdens with symptoms ranging from painful periods to painful bowel movements. And although pain doesn't occur in all cases, it can really impact a patient's quality of life. So when we talk about endometriosis-associated pain, it's important to understand that it's not just the pain coming directly from the lesions themselves. It's actually quite multifactorial. So there are a few different types of pain at play. You kind of have nociceptive pain, which is like your classic tissue damage. So lesions on the bowel causing discomfort, for example. And then there's neuropathic pain, which happens when lesions, particularly in deep endometriosis, invade or compress peripheral nerves. And then there's nociplastic pain. And that's when pain processing in the central nervous system itself becomes altered and pain is felt even in the absence of any tissue damage. And so the main mechanism behind nociplastic pain is something called central sensitization. And here, the central nervous system becomes hypersensitive. So it starts amplifying normal signals and turning things that shouldn't be painful into pain. And typically, this is a protective mechanism. When your body is healing from an injury, becoming more sensitive makes sense. It's like your body's way of telling you to kind of be careful and take it easy. But in chronic pain, this sensitized state might not switch off. And so the brain and spinal cord could stay in this overactive mode even after the tissue has healed. And that's kind of what central sensitization is about. This shows up in a couple of ways. So the first is like hyperalgesia, which means something painful feels more painful than it should. Secondary hyperalgesia, where pain is felt in areas away from the original injury, so where the lesions are located, and allodynia, where something that shouldn't hurt at all, like light touch, actually causes pain. So surgery is one of the most common ways that we treat endometriosis-related pain, and it typically involves removing the lesions or removing the uterus altogether. And while pain does improve on average after surgery, there is a lot of variability in how people respond. So some patients see no reduction in pain at all, and many find that their pain returns within a year even after the endometriosis itself hasn't grown back. And so that last point is kind of what I'm looking at. If removing lesions doesn't always resolve the pain, it suggests that the lesions aren't telling the whole story. And that's kind of where central sensitization comes in as a potential explanation, because surgery can't undo changes that have already happened in the central nervous system. So there's definitely a need for a tool that can kind of identify those at risk for poor pain-related quality of life after surgery. And our lab previously developed the Endometriosis Pain Index, or EPI for short. And this was developed by Dr. Duane Tucker, who was on the podcast in March, I believe. So I encourage people to go back and listen to that. But the model itself predicts pain-related quality of life after surgery defined by the Endometriosis Health Profile 30 or EHP 30 questionnaire, which kind of measures the impact of endometriosis-related pain on daily living. And it uses predictors like baseline pain, depression, anxiety, pain catastrophizing, pelvic floor myalgia, and abdominal wall pain. And two of those predictors, abdominal wall pain and pelvic floor myalgia, are of particular interest. You know, there's limited understanding in terms of the underlying neurophysiology and why they co-occur with endometriosis. Both are diagnosed through physical examination and both are hypothesized to be connected to central sensitization. So yeah, I know there was a lot, but there are multiple pieces that feed into each other in this project. 

00:06:57 Sabrina 

Yes, very interesting, very comprehensive, good. I feel like I have a better understanding of central sensitization for sure, but also all those other topics you touched on. So it seems like there's a lot of problems and a lot of gaps to fill here. So what exactly are you doing or what is your research question or your objectives? 

00:07:17 Alison 

Yeah, so there are two main parts to my project. The first is validating that prediction model, the EPI, for pain outcomes after endometriosis surgery in a new patient cohort. So basically asking, does this model still hold up over time and can we move toward using it in the clinic in the future? The second part involves investigating some of those model predictors. So things like abdominal wall pain and pelvic floor myalgia. And these are thought to be connected to central sensitization. So my research question here is whether these comorbidities are associated with central sensitization to understand their underlying neurophysiology. Because if we can explain why these factors predict poor surgical outcomes, that could change how we approach treatment instead of a one-size-fits-all approach. 

00:08:14 Sabrina 

Very interesting. So it seems like 2 distinct but very related aims to your research. How are you going about answering these questions? So what exactly is your methodology? 

00:08:26 Alison 

Yeah, so both of these studies utilize data from participants enrolled in the endometriosis program. Pelvic Pain Interdisciplinary Cohort, or EPIC registry for short. And this is something that's unique to our center and was designed to longitudinally assess outcomes and their predictors at our tertiary referral center for endometriosis. And it basically consists of patient-reported questionnaires, physical exams, medical records, surgical findings, and annual follow-ups for up to three years. So for the prediction model piece, I use this data registry and the same inclusion and exclusion criteria as was used for the EPI model development, except my surgical cohort was pulled from a later time. So 2021 to 2022, while the original cohort was from 2013 to 2020. And I'm assessing how well the model performs in this new group. So things like discrimination, meaning does it correctly identify who's going to have a poor outcome? Calibration, meaning are the predicted probabilities accurate and do they match up with what we actually observe? And clinical utility, does the model actually lead to better clinical decisions than just treating everyone the same way? And then for the second part of my thesis, in order to investigate the underlying neurophysiology of some of those pain comorbidities and identify central sensitization, I use something called quantitative sensory testing, or QST for short. And this is a standardized protocol developed by the German Research Network on neuropathic pain. And the basic idea is that you apply a series of sensory stimuli to different parts of the body and measure how a person responds. So things like light touch, pressure, and pinprick stimuli to build a sensory profile for that individual. And what we can identify is hypersensitivity, so where the nervous system is in an amplified state, or signs of denervation, where it's less sensitive. And then by testing at different areas on the body, including areas away from where the pain typically is located, then you can kind of distinguish between something that's happening locally versus something that's happening on the level of the central nervous system. 

00:10:52 Sabrina 

Very interesting. Just to follow up on that, can you enlighten us a little bit on what that quantitative sensory testing actually looks like in practice for your participants? 

00:11:03 Alison 

Yeah, so a few things happen before we even start. So we schedule the appointment during the follicular phase of the menstrual cycle, so the early part, to avoid the inflammatory phase where estrogen is higher and could influence pain sensitivity. And then we also ask participants to hold off on taking any pain medications 24 hours beforehand, so that we get their baseline sensory state. And then on the day, the patient lies down on an exam table with their eyes closed, and we test like four different parts of the body. So we use like the left hand as a demonstration site, and that's where I kind of show them, you know, what each stimulus feels like before we actually start the test. And then the right hand is a control site. And then we have two main test sites. So the suprapubic area, which is the lower abdomen to capture local pelvic sensitivity, and the deltoid, which is the shoulder muscle as the remote site. And that remote site is really important because if someone's showing hypersensitivity there or on the hand, it kind of tells us that the pain could be widespread. And then we run through six different tests. So the first is the tactile detection threshold. So here I use like tiny filaments. They're like thin hairs with little rounded tips and I apply them to the skin starting at a higher force and then gradually going lighter until the patient can no longer feel it. And then I go back up again and I repeat this a few times to find this threshold for when they are feeling light touch. And then there's the mechanical pain threshold where I use weighted blunt metal rods that I press onto the skin for about a second. And the sensation is usually sharp or stinging. And we're identifying the point where it crosses from feeling blunt to feeling painful. And again, I go up and down in force to find that threshold. And then we also do a test called mechanical pain sensitivity where the patient rates the painfulness of pinprick stimuli on a scale of 0 to 100. I know it's a large range. Zero means no pain and 100 means the most intense pain sensation imaginable. And then dynamic mechanical allodynia, where I apply a cotton swab, Q-tip, and a brush to the skin, which are all normally non-painful stimuli. And we're checking to see whether any of these produce like burning or stinging sensations. And if they do, that's allodynia, which is a sign of central sensitization. And all of this is done multiple times and in random orders. And then the wind-up test looks at pain summation. So I apply a single pin prick with one of the metal rods and then compare that to a series of 10 stimulations with the same metal rod in the same area. And then lastly, the pressure pain threshold test. And for that I used an elgometer, which is a pressure measuring device, and I press it into the muscle until the participant tells me they feel burning, aching, or drilling sensation. And so the whole appointment takes about an hour and a half. And I really do appreciate everyone who comes in to do this testing. It's not comfortable and some of it is genuinely unpleasant. And then another thing I want to mention is that QST is a really valuable tool, but it's not perfect. And a patient's results can vary between days or even hours, depending on their mood and how well they slept or what they did the day before. So we do our best to control for these things. But at the end of the day, it's a measurement of pain perception, which is just inherently variable. 

00:15:02 Sabrina 

Very interesting. Well, I feel like I was in the clinic with you just now. You walked us through it. That was fantastic. So very interesting, involved work that you're doing, clearly. Can you give us any insight into what your findings have been thus far? 

00:15:19 Alison 

Yeah, so for the temporal validation piece, we see that performance remains relatively stable across those performance indicators I mentioned, so discrimination, calibration, and clinical utility with minor and expected performance drops. And obviously, we still need to continue validating, especially geographical validation in different cohorts outside of our tertiary care center to assess the model's generalizability. But overall, our findings so far are promising. And then for the second portion, the central sensitization portion of my project, we're still doing analysis, but I can share that we are seeing some overlap with pain comorbidities and sensitivity insights away from the pelvic region, which is an indicator of central sensitization. 

00:16:12 Sabrina 

Very interesting. So you mentioned there that your findings are showing potentially increased sensitivity, not just locally, but in other areas of the body. What does that tell us about how pain is being processed for people with endometriosis and how might those insights or insights like this feed into things like a prediction model or help guide more personalized care? 

00:16:38 Alison 

Yeah, so what we're seeing kind of does point towards that central sensitization hypothesis. And at least that endometriosis pain is about way more than just the lesions themselves. And when you see hypersensitivity, not just at the pelvic site, but at unrelated areas like the shoulder, that's telling you that something's happening on the central nervous system level. And with central sensitization, Different nerve fibers can actually get involved. So like your large myelinated sensory fibers, which are your A beta fibers that normally just carry touch information can start acting like pain fibers, which are your A delta and C fibers. And at the level of the spinal cord, the neurons that process these signals can become overactive and dysregulated. So the whole system starts amplifying pain and non painful stimuli. And there's also a mechanism called cross-sensitization where chronic visceral pain, so the kind that comes from the lesions themselves, can spill over and sensitize separate pain systems in the body. And this can occur in patients without chronic pain. So For example, how it could manifest is by asking a patient to drink lots of water in a short amount of time to stress the bladder. And if they experience pain from that, but they're not experiencing pain elsewhere, then we kind of hypothesize this could be cross sensitization. But I think the main takeaway is that endometriosis associated pain is very complex and multifactorial and it's different from person to person. So that's where I think this work could eventually feed into more personalized care and the concept of pain phenotyping and categorizing patients by their underlying pain mechanisms rather than their diagnoses or their stage of endometriosis. Because if we know a patient has central sensitization, that changes the entire conversation around surgery. And then for the prediction model specifically, Understanding the neurophysiology behind some of these predictors could help make the model more explainable, which matters a lot in clinical uptake, especially for models that leverage machine learning and are kind of like a black box. You know, if a clinician can understand why pelvic chromyalgia or abdominal wall pain predict poor outcomes, then they're more likely to trust the model and use it in their clinical decision making. I also want to mention that just because somebody has these kinds of pain comorbidities doesn't mean they have centralized pain. These conditions are also nociceptive, and that's part of why QST is valuable. It gives us a more objective way of understanding what's actually happening neurophysiologically rather than solely relying on the clinical diagnosis. So we're still trying to figure that out and build that picture. 

00:19:41 Sabrina 

Very interesting. Well, thank you for explaining all of those future or the future relevance of all of this important work you're doing. So looking ahead, how do you hope that this work, especially the prediction model piece, might eventually change care or even treatment decisions made for patients after surgery? 

00:20:02 Alison 

Yeah, so I think the best use case for this prediction model would be as a part of the preoperative conversation between a surgeon and a patient. So not a definitive answer, but as a tool that helps to facilitate discussion before surgery and also manage expectations for after surgery. So for example, if a patient is at risk of a higher is at a higher risk for a poor outcome, then maybe there are things we can do about that to proactively prevent a worse outcome. And like, for example, incorporating physiotherapy, counseling, or like a pain program into their pain management action plan earlier and not just after you find out that surgery hasn't worked. And at our center, we do offer that kind of interdisciplinary support. So I think those interventions, those interventions don't really get enough recognition in the endometriosis space, and they're really important. And actually one of the things that our lab is hoping to build towards is integrating the model into a clinical decision aid. So something a patient and the clinician can sit down with together before surgery. And that makes it a tool that's data informed, but at its core about patient centered decision making. And then I mentioned this before, but the other thing I hope this work contributes to is making the model more explainable because If a model just spits out a probability without any context, it's not going to get used. And if we can say the patient has signs of central sensitization and here's why that matters for their surgical outcome, then that's a conversation a clinician can actually have with the patient. And patients who have this pain phenotype should be aware that central sensitization may be associated with less improvement after surgery so that they can weigh the pros and cons. Yeah, and it's also worth saying that a validated prediction model doesn't mean it's ready to be used. Validation is an ongoing process. It's not a one and done, so there's still work to do. We will need to continue validating the EPI as patient populations change and as care models change. So I do think the model has a lot of potential and there are a lot of really exciting directions, but ultimately it comes back to that same thing understanding the multifactorial nature of endometriosis pain so we can move towards personalized care. 

00:22:42 Sabrina 

Fantastic. Yes. Well, thank you to you and your lab for doing such important work for people with endometriosis. To wrap up today, we always ask our trainees, if you could say one thing to everyone who will listen to this podcast today about your field of research, what would you say? 

00:23:03 Alison 

Okay, so one thing that's coming to mind is something that one of my peers said to me in my research, like earlier on. And I remember I was getting like kind of overwhelmed by just how complex pain is. It's not only frustrating for researchers trying to study it, but for clinicians and patients who are trying to communicate about it and manage it. But she reframed it in a way that has genuinely stuck with me. And she said, like, if there are so many pathways that can cause pain, then there have got to be just as many ways to treat it. And I found that really hopeful. And I carry that with me. And I've said it to patients before, because it's like a half glass full kind of way of looking at things. And I really do appreciate that. 

00:23:49 Sabrina 

Fantastic. Well, thank you so much for joining us on the podcast today, sharing your very important work. I know we will want to follow up with you in the future to see more work that you're doing. 

00:24:02 Outro 

Thanks for joining us on the GOSH Podcast. To learn more about the Gynecologic Cancer Initiative and our podcast, make sure to check out our website at gynecancerinitiative.ca.