Alina Sharinn, MD - Targeting Neuropharmacology of Endometriosis-Associated Pain

Hi everybody. Good afternoon. Thank you so much, Dr. Satchkin. I'm just so excited to be here and I will try to go very quickly through this. As mentioned to neurologists here in Manhattan, I treat quite a bit of patients with pelvic pain, particularly endometriosis. And today I'm going to talk about targeting neuropharmacology of endometriosis associated pain. Wait. There we go. We'll skip through this. I'll go through the first few slides. I'll try to go quickly. Obviously, I'm following absolutely amazing speakers. Some of this you've already heard, but obviously this condition major cause of chronic pelvic pain, dysmenorrhea, infertility, but the pain persists past surgery sometimes and really suggests that there are other pathways or neurobiologic pathways that are involved in pain generation and persistence of pain. And we'll talk about that in a second. And so we consider it a neuroinflammatory pain disorder because all of these pathways are involved.

We have peripheral sensitization.

As you know, the threshold of nerve activation is lower due to persistent exposure through inflammatory mediators that are released by the lesions through direct contact of the lesions with the nerve fibers and increased pain sensitivity that leads to neurogenic inflammation. There is cross organ sensitization because chronic inflammation from the lesions leads to sensitization of shared nerve pathways that you've already heard about, the pelvic and the splanknic nerves that send signals to our dorsal ganglia that then converge in the spinal cord and then lead to pain in either a different organ, lead to myofascial pain, lead to radicular pain, but that often is not anatomical. And that's when we end up seeing the patients as well. And then of course, dysuria, bowel issues, et cetera. All that when the signals that are enhanced go up to the brain. We end up also with central sensitization as plasticity and in our brain changes.

I know you've had a lecture on functional MRI and you saw that many regions in the brain that are involved, the connectivity changes. The pathways that are involved in that, we think the NMDA receptor activation, there's decreased inhibition, decreased inhibition that the signals that go down the spinal cord, it decreased GABA. There is microglia and astrocyte activation and there's increased in excitatory neurotransmitters and everything leads to increased synaptic plasticity, change in connectivity. And essentially the brain gets physically and functionally rewired. And we use the pharmacologic agents and other interventions, which today, I'm not going to mention, to try to rewire the brain back, so to speak, because all of these neurobiologic pathways cause diffuse, persistent, and again, often non-anatomical chronic pain. So these are just some of the areas where neuroconnectivity changes, but these are areas that are very involved and hyperactivated in these bienometriosis, inducing this chronic pain and central synthesization.

So insula, anterior cingulate cortex. So essentially hippocampus, thalamus, that's our relay system, pain relay center, prefrontal cortex, limbic system, et cetera. So I'll just skip to the medications. And some of these medications, of course, everybody knows gabapentin, pregabalin, but they're actually very exciting if you think about the mechanism of action and why they're helpful, because they actually address all of the four points of where the pain comes from and how the brain gets rewired. So their major mechanism of action is inhibiting calcium channels and decreasing neuronal excitability, but they also play a role at the neuroinflammation level. They also play a role at an NMDA receptor level. They decrease ... So pregabalin particularly decreases glutamate, decreased substance P, gabapentin affects the ... And modulates are important neurotransmitters such as norepinephrine, serotonin to some degree as well. So they're very important. Gabapentin is one of my go- tos, but for all those reasons, and additionally, because migraines, mood disorders, as we heard insomnia, are such frequent comorbid conditions with endometriosis where you could use one medication, do various titration protocols in patients who may have comorbid fibromyalgia or who have sensitivities to medications.

You can do various titrations and help them with many symptoms, not actually just pain.

Some of the other medications used SNRIs, duloxetine, venlafaxine, again, very commonly used. TCAs potentially can be used. I don't love them because of the side effects, particularly in young women or really in anybody, but can be. Of course, we all know their primary mechanism of action. But again, they've been shown to still decrease to decrease cytokines and really get at the other biologic mechanisms of this chronic pain. Other medications that are exciting are the ones, particularly memantine, as you know. So the glutamate pathway, mematine, as you know, we use it in dementia modulates neurocitation, but much newer literature shows that modulation of glutamatergic activity is very helpful in migraines and other pain disorders.

And I've been using it in my patients. Again, I choose based on comorbidities, depending on what's going on. If I don't need to treat insomnia, I may go to memantine or duloxetine, for example. So it just really depends what's going on. Obviously, not proven yet, but available, very well tolerated, doesn't have interactions, as you know, and very exciting to have at your disposal to be able to use a few other ones that are targeted that target neuroinflammation, microglial activation or minocycline. Minocycline is an exciting potentially anti-inflammatory antioxidant molecule that has been looked at. And in some institutions, and I've used it in certain protocols, treating acute stroke as neuroinflammation plays a role there and patient outcomes are changed. And it is now being looked at at affecting neuroinflammation in this condition. Low-dose naltrexone, as you know, has been tried in many conditions in neuroimmunology. And then one more exciting, some of these are in the pipeline, but the other exciting molecule is the CGRP blocking agents.

As you know, the first CGRP was approved in 2018 for migraines. We now have quite a few of them, oral injections, self-injections and infusions. Again, very well tolerated drugs, very easy to use, not approved in this condition yet. However, we have great deal of evidence that the lesions that cause such disability in this disease secrete CGRP and modulating this pathway, it seems like this molecule reprograms macrophages and delays its job and therefore leads to increased inflammation and potentially growth of endometriosis lesions. And so blocking it seems a very exciting potential treatment that I can help you with your patients between after surgery, et cetera. And again, that all leads to decreasing sensitization and rewiring back our brain. And again, very, very, very easy to use. And since lots of patients have comorbid migraines, it's an easy one to get to. I think the last thing is, which I don't have a slide here, but I often add also naturopathics, they're not a magic wand, but could be helpful.

So things like magnesium, vitamin D, omega-3, and for example, an acetylcysteine, which leads to glutathione, which is an endogenous antioxidant. So those things I always also think to add to help our patients. Thank you very much. I