Gerard Degregoris, MD - The Toxic cocktail: Endometriosis and Opioids - Fluoroscopic Guided Injections
Patient Awareness Day 2019: HEALTHY MIND & HAPPY PELVIS
Living Your Best Life With Endo
March 10, 2019 (8am - 5pm)
Einhorn Auditorium, Lenox Hill Hospital, New York City
https://www.endofound.org/patientday/2019
Thanks so much, Dr. Goldstein and to Dr. Seckin also for the invitation. Good afternoon everyone. Thanks so much for sticking around. I'll try and make it worth your while. And there's a few other great speakers to come. I'm Gerry DeGregoris, and I'm a private practitioner, like Carly said, an anesthesiologist by training, trained at Cornell and now I'm in private practice on 57th and Park. And I also see patients here at Lenox Hill Hospital. I'm here many days in the morning on the acute and chronic pain service.
This talk has a little bit of a funny title. It was born out of an observation that Dr. Seckin made, and he and I got to talking about how so many, not so many, but sometimes an alarming number of patients will come to us on high dose opioids, who haven't yet really addressed the underlying cause of their pain. And a lot of that, or some of that, was probably due to misdiagnosis. But it occurred to us that a lot of patients get started on opioids without really understanding what is being treated and without understanding the side effects of opioids, so that's kind of how this talk came together.
It's going to start off a little bit about what not to do. And then sort of at the end closing minutes here, it'll start a little bit about what to do and what things we can do to help with addressing the sort of underlying cause of the pain associated with endometriosis in specific. But some of what we talk about will be generalizable to pelvic pain in general.
When we talk about the modalities of pain, this talk is going to be kind of narrow in scope, so this is not to say that opioids are the only thing out there, but we're going to start by talking just about opioids because it's topical and I think it's interesting. One of the more interesting things about opioids is not only the fact that it causes respiratory depression, we all know that. And that's in the news a lot, but it has other side effects like opioid induced constipation, urinary retention. But I think we're going to spend most of our time talking about tolerance and opioid induced hyperalgesia.
This is what this talk is not about. It's not about the opioid crisis. That's a totally different topic. I just put this slide up there just for context. There's lots of this stuff out there on the news and 60 Minutes. And we kind of already know this already. What I think would be more interesting and perhaps new to many of you is what exactly causes tolerance in people who are on opioids. And why is it that opioids start to decrease efficacy over time? Because I and a lot of the other physicians have noticed that as patients come in, opioids don't have the same effect that they do initially over time. In fact, over time we've witnessed as physicians and patients tell us that they become less efficacious.
And I think an understanding of why that happens will help some folks understand why it shouldn't be the first go to therapy for folks with endometriosis and lots of other pain syndromes as well. This is a diagram, which is really busy. But I'm going to just sort of walk you through some of the high points as to why tolerance occurs, and why it is that opioids stop working in many patients. Now of course, that's not to say in all patients. There's some people who can get relief and don't seem to develop very much tolerance. But certainly, many patients do find this. And this is sort of some of the science behind that.
On the right side here, this is a sort of diagram of what a cell would look like. And the cells that we're talking about here are the cells in the central nervous system. And the opioid receptor, oftentimes abbreviated MOR, or mu opioid receptor, is shown here on the left. And once an opioid binds that receptor, there's a variety of intracellular events that happen. And one of the things that happen, and one of the newer areas of research is developing is that they're finding that these intracellular events kind of break up into two parallel pathways, with some cross talk, but those two pathways are called the beta arrestin pathway, on the left there, and the G protein pathway on the right.
And it's thought that a lot of the side effects tend to happen after the opioids are exposed. Once your MOR is exposed to an opioid, you get these things called desensitization of the mu opioid receptor. And we think that this is one of the mechanisms by which tolerance to opioids occurs, and which explains to some extent why when people are on opioids for a period of time that they stop working as well as initially they did.
There are other things that happen. You get phosphorylation of these receptors. And what actually happens is you get internalization of these receptors, so when the opioid receptor is bound, that receptor is then flagged and is oftentimes internalized. What that does is it changes the number of opioid receptors that the cell expresses. So over time, we see the number of opioid receptors actually in some patients goes down once they're exposed to opioids. And it's been hypothesized that, that might explain some part of why opioids stop working over time.
Additionally, not only does the number of opiod receptors change once you're exposed to opioids, but we also find that there's this pathway of receptors that get recycled up to the service. So it's also been hypothesized that there might be less recycling of opioid receptors once you're in an opioid rich environment. There's all these downstream effects that affect both the number of receptors at the surface and also the receptivity, if you will, or the sensitivity of each receptor to the opioid.
Even if you had the same number of receptors, there is some basic science research to support that each of those receptors responds less strongly once it's been around opioids for a while. Some basic science research is now showing that you might have fewer opioid receptors when you're exposed to opioids, and the receptors that you do have are less responsive and produce less of a response.
Those are two sort of emerging areas of study that are supporting the idea of why tolerance occurs. And we think that this desensitization might also play a role in dependence upon opioids, so dependence means something different than tolerance. Tolerance, remember, means that the same medicine doesn't give you the level of effect that it once did. Dependence, on the other hand, means that if you were to suddenly stop it, then you would get some undesirable effects, such as withdrawal. That would be things like increased pain, anxiety, tremulousness, insomnia. These are all things that people who are dependent on opioids experience when they stop taking opioids. And in the past it was thought that desensitization and dependence are kind of distinct phenomenon, but they probably overlap in ways that we're sort of discovering more and more.
And of course, that's distinct from addiction, which we're not talking about in today's talk, which is a totally different topic. When we talk about that desensitization, there's a couple of other things that happen, and mechanisms by which desensitization, probably beyond the scope of what we need to know, but just in case anyone's curious. We talked a bit about the number of receptors, the sensitivity of each receptors, but we also get what's called an uncoupling.
One of the ways by which the mu opioid receptors causes pain relief is by using these G proteins. That pathway on the right, the right half of that receptor, those G proteins then go into the cell, and then cause a number of downstream events, which basically serve to make that pain, let's say it's a pain neuron. They make that pain neuron less likely to fire and convey pain impulses to the brain. If you have fewer of these G protein complexes around, then you can't desensitize that cell. And you can't make that cell given it's supposed sensitivity to pain, and it changes the way the cell works.
What does this mean in terms of therapy? Well, there are some researchers out there who are trying to take advantage of this dual nature of the mu opioid receptor, both the beta arrestin pathway and the G protein pathway, in what's called functional selectivity. They reason that if you could selectively activate the G pathway over that beta arrestin pathway, you could potentially take advantage of the good effects, or some of the good effects of opioids, which are postulated to be mostly on the G protein pathway, and minimize some of the side effects, which are thought to be a result of the beta arrestin pathway. It's one receptor that then kind of splits into two pathways.
And there've been a few drug companies that are out there trying to develop opioids that will selectively target the opioid receptor in such a way that it only turns on, or preferentially turns on that G protein pathway while minimizing the beta arrestin pathway, remembering that it's thought to be that beta arrestin pathway's responsible for a lot of the side effects of opioids. By the way, there's no drugs out on the market yet that are taking advantage of this functional selectivity. But I think in the future we probably will see some drugs that do take advantage of this. There's a reference there for anyone who's interested in reading more about it.
In a related topic ... So that was tolerance. I think a related topic that's interesting just to revisit is the idea of opioid induced hyperalgesia, which is thought to be related to tolerance, but it means something slightly different. Remember, tolerance means that the same level, or the same level of medication, doesn't provide the initial benefit that it once did. Hyperalgesia means something slightly different. With hyperalgesia, what happens there is that patients will actually find that when they're exposed to opioids, their ability to tolerate pain decreases, even in places where there previously was not pain. This doesn't happen in everyone. And it's not a black or white thing. There are probably varying degrees of hyperalgesia.
And there are a couple of studies that give us that shine a little bit of light as to how it develops. But I'd say that they're still kind of in their infancy of really describing and really getting a firm understanding of what's happening when people become hyperalgesic. And by the way, what that means, like we said before, hyper, too much. And algesia is pain, so too much pain. One study here looked at a variety of chronic pain patients who were started on opioids, average dose is around 75 milligrams per day. And what they found is that the pain threshold, so the level of noxious stimulation they were able to tolerate went down after they were on opioids for some time. But it only went down in one of the two models for pain.
First they modeled pain as a cold stimuli causing pain, and then another model of pain they measured as heat stimuli causing pain. The cold part of it, when they looked at that part, actually those scores did go down. In other words, people were less able to tolerate this cold model of pain. But there were no specific differences in the heat model of pain. So I think that also is interesting because it really goes to show that we don't really have a universal model of pain because there's lots of different kinds of pain. And pain is certainly experienced different by every single patient. I think nothing we say, certainly nothing I say here, could be generalizable to every single patient or every single disease state. I just want to sort of make some general trends and certainly things to think about for the future. In this study, pain threshold dropped. And the amount of pain they were able to tolerate also dropped as well after exposure to opioids.
Some more references here. There's some good data in the anesthesiology literature that shows that an exposure to Remifentanil, which is a very short acting opioid used intraoperatively in certain cases, while it may have been helpful in blunting the pain of surgery intraoperatively, it was shown to decrease the efficacy of morphine in the postop period. Isn't that interesting? There is a related study in the anesthesia literature that I didn't post here, where they exposed patients to opioids, IV opioids, and induced pain in their forearm. And they looked at two groups, one group of patients who were given opioids, one that was not given opioids. And they found that the group that was given opioids for this induced pain their forearm, they had less pain during the treatment. But what they found was that afterwards, the area that they reported was painful was actually higher in the previously treated group. In other words, that people who got opioids then reported a larger area of pain than did the control group, who did not have opioids after the stimulus was removed.
It's another example of this potentially hyperalgesic response where well intentioned, well meaning doctors, are trying to treat pain with opioids. But in some people, it can actually set them up for more pain down the line. There's another study here that found significant pain reduction in chronic pain patients after weaning high dose opioids. In other words, these are people who were on stable opioid doses, who found that they weren't sure if the medication was helping or not. And in this voluntary, patients who had volunteered for this, they found that many of them had decreased pain scores once they came off opioids after an adjustment period.
Of course, all the studies we're talking about in this slide have several limitations. They're all very small studies, not a lot of patients involved. And they're all for varying pain states. For instance, this study was chronic pain for any reason. And of those 23 patients, most of them were men, certainly not widely generalizable to things like endometriosis pain. So all these studies do have limitations to be sure. And then lastly, there was a study there that showed methadone users who are on long-term methadone did have decreased pain tolerance compared to age matched to controls.
There's some data out there that suggests that opioids can have unintended effects in terms of potentially amplifying pain and sensitizing folks to pain down the line. That's sort of a cautionary tale about of a way to be informed before we start patients on opioids, or before we start taking opioids as patients. But maybe we'll wrap up here just talking a little bit about things that we can do that are less likely to have some of those problems.
As an anesthesiologist, I spend most of my time thinking about and treating pain syndromes with injection based therapies. And there's a wide variety of them. This list is just to help put them in context. There are muscle based injections, peripheral nerve blocks, regenerative medicine, which is a rapidly expanding, very exciting area, including platelet rich plasma, things like alpha 2-macroglobulin, and stem cells, which I think will play a bigger role in the future, but are beyond the scope of this talk. And there's spine injections as well, which we'll talk a little bit in the closing seconds here, closing minutes.
This is an example of what the sympathetic nervous system is. When we think about the nervous system in general, most of the nerves that we're thinking about on a day to day basis are what we call the somatic nervous system. Those are the nerves that help us walk, that move our muscles, and that are usually responsible for what I would call normal, ordinary pain. So you stub your toe on the sidewalk, that's probably somatic pain. You hit your finger with a hammer, or maybe a paper cut, these are usually somatic pain.
And one of the things that I've observed, and other physicians have observed, is that in people who have chronic pain syndromes like pelvic pain and like endometriosis, is that there tends to be other characteristics of the pain that are not well described by the somatic nervous system. And we think that sometimes people who are in chronic pain, they start to get pain conveyed not only by the somatic nervous system, which is a kind of normal sort of pain, but the sympathetic nervous system, which usually does not control pain impulses, starts to be almost high jacked by pain, but put it kind of artistically.
And once these sympathetic nerves, which are usually not supposed to be conveying pain impulses, start conveying pain impulses, they serve to amplify the experience of pain and increase morbidity and the problems that people can experience. One of the ways that we treat pain as interventional pain physicians is we try and block these sympathetic nerves to see, first off. Are they contributing to the pain syndrome? And what we have observed in the literature, and there are some case studies and case theories to support this, is that even though we're using technically temporary blockades of these sympathetic nerves, even after the local anesthetics and steroids that we use are expected to wear off, many times that benefits will persist for longer than we've expected.
And again, there's no really rigorous randomized control trials that prove this. But certainly, there's a long list of physicians who've written about this, observed this, and spoken to patients who do find that there are some people who get long-term benefit. Obviously, not everyone will get long-term benefit from this, and not even everyone gets short-term benefit. But it's the kind of thing that I think is worth trying and at least worth discussing with your physician to see if it might benefit.
This is a diagram of the sympathetic nervous system. The yellow nerves there are sort of the normal nerves, the somatic nerves. And the red nerves here are example of the autonomic nerves, and the specific autonomic nerves we're interested in here are the sympathetic nerves. Just a word here about what sympathetic injections are not. I just always put this slide up typically because a lot of patients, and a lot of physicians even, assume that any injection in the back is an epidural, and use the word epidural to describe injections in the back. Well, epidural means something very specific. An epidural injection is called so because the needle is in the epidural space. That's what we do for surgical analgesia, what we do oftentimes too for labor analgesia. Epidural space means a very specific thing. It's inside the spinal cord, and usually not the first thing interventionists try to treat pelvic pain.
One of the things that we do try, I'm going to skip this slide for time, is things like the impar block and the hypogastric plexus block. These are examples of sympathetic nerve blocks, getting back to the idea of trying to treat sympathetic nerve pain that I introduced earlier. When we block these sympathetic nerves, we can oftentimes remove part of the pain generator. And this operates on that theory in that once the somatic nerves start getting firing, basically because of endometriosis or some other insult, these sympathetic nerves can then get high jacked. Right? And they might perpetuate that experience of pain. And if we can block these sympathetic nerves that we can oftentimes temporarily, or even times, many times for longer periods of time, sometimes months or even longer, can improve a patient's pain and improve their functionality.
This is just a picture of what that looks like. This is a picture of someone laying face down on their belly. This picture here would be for a superior hypogastric plexus block. It would be one or two needles. Oftentimes, you can get it just with one side. And using local anesthetic with or without steroid to temporarily anesthetize these sympathetic nerves, trying to remove the contribution of the sympathetic nerve system to the pain disorder. This would be the hypogastric plexus block. And then if we were to look back, the impar block would be right here at the bottom of where the tailbone would be. That's where the ganglion impar lives.
Those are two examples of blocks which can be helpful in folks with pelvic pain in general, and endometriosis specifically. I think we're going to leave off with no questions for now and move on. But I will hang around in the lobby for a few minutes. If anyone has some specific questions, I'd be happy to try and answer them. Thank you so much for the opportunity.
Thank you so much.
