Early detection and diagnosis
is the best prevention
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Medical Conference 2017

Gerard DeGregoris, MD - Why is there still pain?

Gerard DeGregoris, MD

Why is there still pain?

Patient Awareness Day
The Lifecycle of Endometriosis: From Diagnosis to Coping with Disease
Sunday April 17, 2016
Lenox Hill Hospital, Einhorn Auditorium

We are going to talk a little for the next few minutes here about why pain persists during and after endometriosis as a condition and a couple of other related topics as well. What medications exist? What are some of the risks and side-effects and then we will focus on medical treatment. I think talk flows logically from Dr. Kim’s talk. I just want to start by saying those medications she mentioned are clearly the workhorse of pain management for endometriosis and some of these pain medications can work to augment some of those treatments that we have already heard about.

Why is endometriosis painful in the first place? When we find endometriosis tissue on pathology samples it is commonly seen to be attached and implanted and you will find endometrial glands and stroma on the interior of the peritoneum. For the first part you have got direct invasion of very sensitive structures and as a result of that invasion we then get an inflammatory response.

The inflammatory response is what we are all familiar with when we think of pain in general. For instance we strike our finger with a hammer so we have got two components of pain; the inflammation is the swelling, red, uncomfortable sensation that we are clearly all familiar with from everyday life. That is one component of endometriosis pain, inflammation. The other component is the direct stimulation of these nerve fibers called nociceptors. Nociceptors are specifically designed nerve fibers that when stimulated transmit a pain impulse to the brain. These nerve fibers developed evolutionarily because we need to know when tissue damage has occurred so that we can then protect that limb or that part of the body for a time while tissue healing occurs. Those are the two chief mechanisms by which endometriosis causes pain. We have direct infiltration of tissue, which stimulates these things called nociceptors, and then we have got inflammation, which then also contributes to usually more long term pain.

One of the components of chronic inflammation, so when inflammation changes from acute to chronic is we find that some of the chemical mediators, which I will show you on the next slide, tend to be overproduced by tissue. Those chemical mediators are among the most typical of them are mostly prostaglandins but to some extent the up regulation of estrogen has also been shown to maintain chronic inflammation and perpetuate chronic pain. So what we will see next is what inflammation looks like in a diagrammatic portrayal.

In the top left corner we have got some trauma but it does not have to be trauma in the example I gave earlier, striking your finger with a hammer. The invasion of sensitive peritoneal tissues by endometriosis is a form of trauma. When I say trauma I am speaking very loosely in terms of any sorts of tissue destruction or even tissue irritation. Those tissues, those peritoneal tissues then liberate something called PA2, or phospholipase 2, which starts this inflammation cascade. That cascade of chemical events is then showed later on the slide. Eventually that leads to the development and the spread of prostaglandins and all the different kinds of prostaglandins are located down there. There are prostaglandins E, D and F and there are other tissues also that are liberated from you see the center there and from the endothelium can release prostacyclines and then platelets, which are a component of blood can liberate other parts of the inflammation cascade called Thromboxane. So all these chemicals tend to be up regulated whenever there is the presence of inflammation and they then will reinforce the presence of inflammation and pain.

This is interesting to understand because once we understand why endometriosis is painful we can understand how different medications act to block different pathways of pain. For instance, the NSAIDs there in bold and in the center of the slide those are things like Meloxicam, ibuprofen and Aleve act by blocking the conversion of Arachidonic acid to prostaglandins and blocking the liberation of prostaglandins. So that is one common medication that some people use. Interestingly, we will see some other medications a bit later so neuropathic medications act by a different pathway, so apart from the inflammatory pathway. Aspirin also acts at the same motion there. Aspirin, NSAIDs inhibit this enzyme there called Cyclooxygenase also known as Cox. You may have heard of Cox1 and Cox2 inhibitors so there are two different subtypes of Cox. Most NSAIDs block both of them but you may remember Vioxx was around for a while until it got pulled from the market and there do exist some specific Cox2 inhibitors. One example that is available now would be things like Celebrex, which is Celecoxib. The reason why that is advantageous sometimes is because Cyclooxygenase is not all bad. In fact, Cyclooxygenase is responsible for allowing the body to have some prostaglandins which do good things. For instance one of the most important thing prostaglandins are responsible for is maintaining the protective lining in our stomachs that keeps the acid in our stomachs that is responsible for breaking down food from breaking down our stomach lining.

If you are like me and you have occasionally taken too much ibuprofen when you are in pain you may have noticed your stomach hurts for a day or two afterwards and that is oftentimes the reason why – because you are inhibiting both the good prostaglandins as well as the bad prostaglandins. One of the ways around that if you are someone like me who suffers from what we call dyspepsia or stomach irritation after NSAIDs is to use a Cox2 specific prostaglandin inhibitor such as something like Mobic or Celecoxib also known as Celebrex.

That is a global picture of the inflammation part of why endometriosis is painful. We have also discussed a little bit now about the direct stimulation of nociceptors can also cause pain signals to go from these nociceptors to the spinal cord then go up to the brain where they are perceived as pain. Another general class of medications that we should mention would be things like neuropathic pain agents. These are things like Gabapentin and Lyrica and some of what are called SSRI agents as well. Those are things like Cymbalta and other drugs in that drug class. These medications act a bit differently. We will start by talking a little bit about the medications like Gabapentin and Lyrica and now we are talking about neuropathic pain medications.

Medications like Lyrica and Gabapentin work by trying to change that signal, that pain signal, once it has been perceived by the nociceptors as it is in the spinal cord into the brain. These medications actually go to a specific receptor on nerve cells called a calcium channel receptor and there are calcium channel receptors all throughout the body. This is a very specific calcium channel receptor so it usually does not change your calcium metabolism generally speaking. And by blocking to this very specific receptor in the spinal cord it will change the way these pain signals ascend in the spinal cord. And by blocking this message many people will find that the intensity of the pain is then perceived as less because some of these signals never actually make it to the brain because the specific receptors has been turned off on these neurons inside the spinal cord. Now we have talked about a third component of pain that would be the neuropathic component of pain.

We will get up to speed here with some of the things we have spoken about anti-inflammatory treatments, the anti-neuropathic treatments, which involve those receptors in the spinal cord, things like Gabapentin, things like Lyrica. Dr. Kim gave an excellent summary of some of the hormonal treatments which includes steroids, estrogen and progesterone receptor modulators and immune system modulators as well.

This is a bit of a summary slide that just sort of reviews what we have spoken about with the components of nociceptors versus neuropathic pain. Nociceptors oftentimes convey pain which can be facilitated by the presence of inflammation. Once those pain signals are into the central nervous system that is when the component of neuropathic pain comes. But there is another component of neuropathic pain as well. Occasionally when endometriosis sufferers have endometrial tissue that directly invades nerves, which it can do within the peritoneum there are a lot of nerves in that area, and in the abdomen and in other parts of the body as well, those nerves can then, even though the distal portion of the nerve may be normal, so the nerve starts here on my left and then some compotion of the pipeline of nerve is then damaged. That nerve will then convey pain impulses as if some tissue injury were perceived at the end of the nociceptor, at the terminal where it started. Even after that endometriotic tissue is resected sometimes if the nerve was irritated enough it can continue to send pain impulses to the brain even after that nociceptor is no longer stimulated. So there is something about the invasion of endometriosis tissue into nerves that causes this feedback loop where pain signals are then continuously sent to the brain even after the inflammation is gone. That would be an instance when inflammation has gone but pain persists. That would be an example of what we call neuropathic pain.

Neuropathic pain is oftentimes that pain that is being conducted by a nerve even after inflammation, even after the initial traumatic event has resolved. I think that is an explanation as to why sometimes pain can persist even after there is no more endometriosis left after a through excision. This neuropathic pain can sometimes be described as a little bit different than nociceptive pain. Sometimes patients describe it as being heavy or burning, inflammatory pain is typically not burning, if pain is more burning in sensation that could be more of a neuropathic picture. We saw already how it can be caused by damage to nerves themselves. These are patients who tend to get specific improvements from some of those neuropathic agents that I alluded to earlier.

We have spoken already about some of the agents for nociceptive pain. We talked about NSAIDs, which work systemically but mostly by blocking the prostaglandins. Acetaminophen can be an adjuvant, many times it is not potent enough by itself but it certainly can help a little bit. Acetaminophen works not by decreasing inflammation, acetaminophen actually works at the brain and the peripheral tissues by complex mechanisms, which are not entirely understood. But there is some component of activity at the brain stem and inside the brain itself by which acetaminophen can modulate the reception of pain by the brain. Then there are opioids as well. We will talk about the opioids a couple of slides from now.

Common NSAIDs here, we have spoken about ibuprofen, it is well absorbed, it is metabolized by the liver and some of the typical doses are there. Naproxen is a little different. Naproxen is also well absorbed. It has a longer half-life than does ibuprofen. And because of that longer half-life that is why if you look at your bottle of Aleve it says dose at twice a day, whereas ibuprofen is typically dosed four times per day. Another advantage of Naproxen there tends to be less gastrointestinal, less stomach irritation than some of the other NSAIDs have like ibuprofen.

We have spoken a little bit about Celecoxib which already is one of those Cox2 selective inhibitors, which is also a long acting drug. It is dosed either twice per day or once per day. Common side effects of all these NSAIDs include headache, some edema, some dyspepsia although perhaps less dyspepsia with those Cox2 selective agents like Celecoxib and then some other gastrointestinal symptoms as well are not uncommon.

Importantly Celecoxib is contraindicated for anyone who is allergic to sulpha but celecoxib does not interfere with platelet function so anyone who has had surgery probably remembers you are not supposed to take non-steroidal medications before surgery. That is a point that is being urgently debated among various surgeons. I do not think anyone really understands exactly how much of bleeding can be caused by non-steroidal drugs. It seems that newer research is saying not as much as we previously thought. We are finding that each year surgeons are becoming more comfortable with restarting non-steroidal medications sooner and sooner after surgery. So they can be helpful with post-surgical pain as well.

One of the reasons why Cox2 inhibitors were pulled from the market, at least some of them were pulled from the market was because of a 2005 FDA inquiry which found that there was some increase in cardiac events in a specific subset of patients. Celecoxib is still FDA approved and has been deemed safe for use in patients.

We talked a little bit about acetaminophen, some of the other advantages, it is safest for those who are trying to conceive, so it is the only medication that we have talked about that is pregnancy class B; A is the most safe, D is the least safe. Most medications that I will talk about today are class C, except for acetaminophen which is class B. We have spoken how it acts both in peripheral tissues, the hypothalamus, which is in the brain and the spinal cord as well.

We spoke a little bit about Gabapentin and Lyrica. Some of the side effects that occur with that are things like dizziness, sedation, some patients will say their thinking is a little clouded. Many times this is because the dose is not optimized correctly. But some patients get side effects from these medications before they get efficacy. That probably has something to do with the patient’s individual genetic makeup and the way we metabolize the drugs.

Some of the other neuropathic medications would be things like the tricyclic antidepressants. Even though we call them antidepressants when we use them for pain we actually use them at dose levels that are below the effective rate for depression. So even though these medications were invented to treat depression, things like amitriptyline and nortriptyline we typically use them at doses that are actually far less than that. For example, the antidepressant doses tend to be 100 to 150mg, we tend to use something around 50mg for effects for pain. Some common side effects with those would be sedation, dry mouth and occasionally confusion.

Then we have another class of medications that were also invented as antidepressants, the SNRI class. That would be things like Cymbalta, which can also be helpful by modulating those pain impulses after they have entered the central nervous system and decrease the amount of those pain impulses that make it up to the brain.

Now we will talk a little bit about opioids. Opioids work primarily at the spinal cord itself but also work in the brain. They bind to receptors called the mu-opioid receptor. There are several subclasses of opioid receptors. There are at least five main classes and there are other subtypes as well. Of them we think that the mu-opioid receptor is one of the ones that is most important for the pain modulating effects of this. The problem with opioids is that they are not ideal for long term relief because of a mechanism known as tachyphylaxis also known as tolerance such that opioids work great in the short term but the more you take of opioids the less benefit you get from them. They are ideal for post-surgical pain, for episodic pain that may come on occasionally but what happens is when you take opioids chronically your mu-opioid receptors then change and they become less receptive to those very opioids that initially were helpful. We will see a little bit more about that a couple of slides from now.

Some of the side effects that we have to be wary of for opioids include respiratory depression, they can cause hormonal imbalance, obviously opioids can cause constipation, they can cause some urinary retention and they can cause a phenomenon called opioid induced hyperalgesia. The last side effect that we really do not understand yet is immune system modulation. There is some data out of the University of Chicago that suggests that, and this is primarily data in test tubes not data in humans although there is some emerging data in humans as well, that suggests immune dysfunction can follow from long term opiate use such that they found that tumor cells may grow at a faster rate in the presence of opiates. This seems to be a phenomenon that is not unique to one specific opiate but that is shared by all of them and that has actually been a source of discussion amongst some researchers about using that to the advantage for treating cancer therapy, actually developing drugs that will target the opiate receptor to keep cancer cells from proliferating.

Clearly the decision to start opioids is a complex one and unfortunately we just do not have a good sense of how real this risk of the potentiation for growth of tumor cells is in the context of opiates but hopefully we will have more research on that in the future.

Now we will talk a little bit about opioid induced hyperalgesia. Algesia comes from a Greek work for meaning pain, so increased pain basically and hyperalgesia is when an uncomfortable stimulus becomes increasingly painful with time. Such that if someone were to pinch me on my head now I would say okay that is painful, that is uncomfortable but it is not excruciating. But if something were to happen to cause hyperalgesia on me that same stimulus with the same force I would then perceive it as more painful than it was maybe a month before I had this hyperalgesia. This has been demonstrated a couple of times in human subjects. It certainly does not happen in everyone and it is not an all or nothing phenomenon. There is a spectrum of hyperalgesia so some patients, I certainly know patients, who have been on opiates for years who do not seem to have any component of hyperalgesia. And I have met other patients who will get this component of hyperalgesia after only a couple of months of opiates.

There is one pretty good study that typifies what we are describing. They took some healthy patients who were suffering from chronic low back pain and they picked those patients just because they were so many of them. It is such a common disease it was easy to do the study. These were patients who were not on opiates initially. They then titrated them up on morphine, one of the most common opiates to their maximum effected dose they tolerated without side effects. After one month of opiate therapy all the patients, to some degree, became hypersensitive to pain. This was measured in a very scientific way. They did what is called the cold pressor test. They took a bucket of ice water and before the study they had the patients put their hands in a bucket of ice water and they had a stop watch. Obviously that is a pretty painful stimulus so initially patients were then, after a certain number of seconds, they said okay it became painful and that is the threshold after which something becomes painful and then after a few more seconds it becomes excruciating and they were instructed to take their hand out once it was excruciating.

What they found was that the threshold at which that stimulus became painful actually dropped. So when it say pain threshold drop it does not mean the pain dropped, the threshold at which patients detected pain dropped, which means that previously non-painful stimuli then became stimuli by that 16 percent. That was the number of seconds that elapsed. Tolerance was that second number I mentioned which was how long could they withstand that painful impulse before it became excruciating. This is some data to describe on a very basic level the mechanism of opiate induced hyperalgesia.

That kind of begs the question in patients who do have a decreased pain threshold due to chronic opioid use if we were to decrease the opiates could pain improve? And the answer to that is for some people but not for everyone. There was another study that was published in a European journal several years ago where patients were, chronic pain patients, this was not just limited to low back pain this was open label for many different diagnoses, were then treated by decreasing opiates. Not stopping them necessarily but decreasing them to as far as the patients were willing to go. That happened over one to three weeks. They found that the VAS pain score is the pain score which you may have heard before the zero to ten pain score with zero being no pain and ten being the worst pain you can imagine. In some patients the pains were actually decreased when they decreased their opiates, which was counterintuitive for me when I first read that. But also interesting is some patients got an increase in pain and some patients found decrease but overall the average pain did not increase for the whole group. Each individual patient might have had an increase or decrease in their pain but overall the average pain score across all the patients did not increase.

In fact, there was a trend towards the pain to decrease average but it did not reach what we call statistical significance. Even though you see the pain score decrease from 7.1 to 5.4 those numbers are not different enough for us to say with certainty that that is a real change. There is a chance that that could just be a coincidence that those pain numbers decreased. If they had gone from 7 down to maybe 4.0 that probably would have been enough for us to say this is statistically significant.

What I learned from reading this study was that in some patients who are having significant worsening pain after starting on opiates or not improving that it is worth trying to decrease the dose and in as soon as three weeks some patients will find that their pain is not quite as bad as it was before.

The last thing I will talk about is obviously one the things you may have seen in the news. A lot of local congressmen are concerned with overdose stats. I will say that even though opiates are very powerful and potentially dangerous drugs I think that if they are used with the guidance of a physician and followed closely by a physician that they can be used safely. I think that was my goal in putting that slide up there.

Here are some of the references for anyone who is interested. The last one about the opiate hyperalgesia is that Krumova study there. Thank you for your attention.


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