Hello, everyone. Thank you for joining us again today. For those of you that don’t know me, my name is Ina Liko, and I’m the Director of Clinical Pharmacogenomic Operations at RxGenomix. So today, we’re going to be continuing to talk about pain medications, but different from what we’ve done before. Since it is the end of the month, I would like to start off with summarizing some of the genetic variations that do affect pain medications, and then I’ll actually have a couple of case studies that we’ll go through. As always, if you have any questions, please feel free to put them in the chat or the Q&A portion, and then I’ll address them at the end.
All right. So without further ado, let’s get started with the first gene that we talk about this month. So just a reminder here, this is OPRM1. So OPRM1 is opioid receptors that are part of the endogenous opioid system, which is the body’s internal system for regulating pain, reward, as well as addictive behavior. It does consist of opioid substances that are produced naturally within the body, and their receptors into which opioids fit like keys into a lock.
Now, opioid receptors are found in the nervous system, where they’re embedded in the outer membrane of the nerve cells or the neurons. And when opioids attached or they bind to these receptors, the interactions trigger a series of chemical changes within and between neurons that actually leads to the feeling of pain relief. Now the mu opioid receptor was the first opioid receptor to be discovered, and it is the primary receptor for these endogenous opioids that we call beta-endorphins or enkephalins, which help to regulate the body’s response, again, to pain among other functions.
Now the mu opioid receptor is also the binding site for many opioids introduced from outside the body, or what we call … So they are what we called exogenous opioids, and they’re a common medication, pain medication, such as oxycodone, fentanyl, methadone, oxymorphone, codeine, morphine, and tramadol. Now when endogenous, or actually, exogenous opioids … That’s what we will be focusing on today, are those medications.
When they actually bind to the new receptor, the interaction triggers the cascade of chemicals in the nervous system. And these signals reduce the activity or the excitability of neurons in certain area of the brain, which then leads to pain relief. Now, in addition, the chemical signaling ultimately increases the production of another chemical called dopamine. And dopamine is a chemical messenger, a neurotransmitter, that helps to regulate areas of the brain that are involved in reward-seeking behavior, attention, as well as mood.
So that was an overview of just the opioid receptors in general. My computer is being a little bit slow today. But what about OPRM1, and how does this actually relate to medications? So the gene that codes for the new opioid receptor, it’s called OPRM1 and is highly polymorphic with more than 200 known variant alleles. Now the most widely studied variant is this variant that I have laid out there, is this A118G, and it has been studied for its role in opioid response, as well as alcohol and opioid use disorders. Now this variant is associated with reduced expression in vitro and in vivo, although the mechanism of action of this, exactly how it works, is a little bit unclear. But like I said, it is related to opioid response.
So now I’ll move on to another gene. So these first few slides will just be an overview of some of the main genes that are involved. So it may feel like we’re jumping to different genes, but they’re all involved for pain medications. And then this will give us a good basis to then go back to a patient case and try to solve based on these genetic variations and what this relation is with the medication.
So now that we talked about OPRM1, if you remember from one of my prayer lectures at the beginning of this month, COMT is also another gene that is involved in this, in pain. COMT stands for catechol-O-methyltransferase, and it is an enzyme that is coded for by the COMT gene. So COMT is going to inactivate the catecholamine neurotransmitters. So this dopamine and norepinephrine, epinephrine that you see here, COMT is going to inactivate it through this other website here, so through this enzyme called SAM, or S-Adenosyl-L-homocysteine.
Now how does this relate to pain medications? So the most well-studied polymorphism in COMT is also this variant here. So this rs4680, and then we’ll see … actually, I have some specific guidance in terms of how this relates to medications in the next few slides here. But pretty much, high COMT activity, so that Val, if you have this variation, it’s low. It means low catecholamine levels, and these individuals usually have higher pain threshold. If you have low conductivity, if you have the Met variation, you have high catecholamine levels, then you have pretty much lower pain threshold. And COMT, you actually may encounter this particular gene in other disorders like psychiatric disorders as well, because it does affect some psychiatric medications.
Now, since we talked about OPRM1 and COMT, so there is some CPIC guidance when it comes to this in terms of how they relate and what’s the evidence out there for how they affect pain medications. So for OPRM1, the variant is inconsistently they have shown to alter postoperative dose requirements for some opioids, for certain opioids. And there is evidence for a small increase in postoperative morphine dose requirement, maybe 10%. This patient may need 10% more morphine, in some clinical studies in patients that do carry this particular variant. So that’s how it relates to OPRM1.
However, when it comes to COMT, really, there need to be more studies there because there isn’t strong evidence to support an association of this variant with opioid adverse events. That’s what the studies have mainly looked at. And then there’s also mixed evidence for an association between COMT. And again, this is the most studied variant, this genotype, analgesia or opioid dose requirements. So COMT, the verdict is still out there. We just need to see a little bit more evidence in order to apply it clinically, when it comes to pain medications.
Now another gene that you all should be very familiar with, because I talk about this gene a lot, it does affect a lot of medications, is CYP2D6. So there are over 130 known variants of CYP2D6. And I won’t go too much into detail about them because I’ve talked about this a lot in the past, but there are different types of variants. So we have single nucleotide polymorphisms, insertion, deletions, duplications, and multiplication. And these variants, they can alter the pharmacokinetics of the enzyme, which can then lead to an increased function in those carrying additional functional gene copies or decreased or no function, if you have a gene deletion.
And in terms of the phenotypes here, so there are ultra-rapid metabolizers, where we generally expect a poor drug response, unless we’re dealing with a prodrug. In that case, this patient may have side effects because CYP2D6 is activating that particular medication at the higher level. And then intermediate and poor metabolizers, we would generally expect more side effects. So I just wanted to bring in CYP2D6 here very briefly, just remind you that it is one of the main genes that also affects pain medications.
Now another gene that will affect pain medications is CYP2C9, and particularly, it affects NSAIDs. And we had a case study about that last week, but we’ll see how we can actually apply to this case study this week. The case study for this week is a little bit different. So CYP2C9, it metabolizes about 15 to 20% of all medications that are undergoing that phase one metabolism. And it also has a lot of variations, not as much as CYP2D6, but they’re about 61 known variance of CYP2C9. And then, again here, in terms of the categories, we have normal function, decreased function, and no function. So if you notice there isn’t any ultrarapid or rapid metabolizer status when it comes to CYP2C9. So in terms of the phenotypes, we have normal metabolizer, intermediate, and poor. So again, for intermediate and poor metabolizers here, we would expect these patients to have more side effects at that current dose.
All right, now this is more exciting now. We’re talking about a patient. Now that we know a little bit about the genes, let’s see how we can apply that information to this patient. So this is Lisa. Lisa is a 50-year-old Asian female. She doesn’t really have much of an extensive medical history. She just actually had knee replacement surgery a little bit ago. So that’s as far as her medical history goes. Otherwise, pretty healthy. Never really needed to use pain medications before. But as you can imagine, for surgery, she does actually need pain medications. So in the hospital, they gave her codeine. And then, when she went home, they gave her tramadol to control the pain for a few days.
However, Lisa did not really respond very well to these medications when she was in the hospital. She had some pretty bad side effects, like shallow breathing, some confusion, and dizziness. And then, when she was sent home with tramadol, she also noticed that her dizziness and confusion continued. So clearly, these medications are not really working all that well for her. And for her, we’re concerned about her safety.
This is her genetic results here. What we’re mainly looking at, when it comes to codeine and tramadol, we’re looking at CYP2D6. So we have a couple of cases today. I’ve just spelled out what that phenotype is. So for CYP2D6, she’s an ultra-rapid metabolizer. So keep this phenotype in mind as we look at some of the guidance of what we do with an ultra-rapid metabolizer. The patient we had last time, he was a poor metabolizer. So this is a little bit different and a completely different guidance for her.
So CPIC does have some guidance when it comes to these. For an ultra-rapid metabolizer, which is what our patient is, the main guidance here is to avoid codeine as well as tramadol, because of potential for toxicity. However, if opioid use is warranted, like in the case of Lisa, she was in the hospital having that surgery, she’s in a lot of pain, then consider a non-tramadol, non-codeine opioid. So actually, hydrocodone would be a good alternative here, or even morphine if she had another surgery in the future and she needed these medications.
When it comes to ultra-rapid metabolizers, there aren’t any particular recommendations for hydrocodone because it’s not really well studied, regarding adverse events or analgesia. But since it does have a similar mechanism of action, and if we don’t really want to risk it, we can definitely recommend a completely different medication class, such as morphine.
Now for completeness here, I will also go over some of the other phenotypes. So for an intermediate metabolizer, CPIC recommends to use label-recommended dosing and to monitor for some of these side effects, or if the medication is working or not. And then if you’re a poor metabolizer, so it is similar guidance in terms of avoiding codeine and tramadol. However, here the avoidance will be because of diminished analgesia. And then this is the case here because, again, as a reminder, codeine and tramadol, they’re prodrugs. So they really need CYP2D6 to activate them. And in the case of poor metabolizers, CYP2D6, they just don’t have enough of that enzyme to activate codeine or tramadol to an active metabolite, which is morphine, for it to work.
And then in the case of our patient, what was happening is that she’s an ultra-rapid metabolizer of CYP2D6. So she was activating a lot of that medication, a lot of codeine, and a lot of tramadol was being activated to morphine at a much faster rate. So her morphine levels in the blood were a lot higher than they would be in a normal metabolizer or even an intermediate or poor metabolizer. So that’s why she was having those side effects. And then again, it’s the concept of the prodrug here.
Now, the Dutch Working Group also has some guidance when it comes to ultra-rapid metabolizers. They say that for codeine, for doses that are more than 20 milligrams every six hours, which, in the hospital, that’s the max dose, and what you actually give for surgeries, it is contraindicated, and it’s say to choose an alternative therapy. For tramadol, similarly, choose an alternative therapy, or if there aren’t any alternatives, the Dutch Working Group recommends to use 40% of the standard dose. And then, similarly, here for poor metabolizers, again, for a completely different reason, but the Dutch Working Group also recommends to choose an alternative.
Now the FDA also has some language when it comes to this. For an ultra-rapid metabolizer, when it comes to codeine, they do say that it results in higher systemic active metabolite concentrations, as well as higher adverse reaction risk. And they go as far as to say some of this could be life threatening, respiratory depression, even death. So same thing with tramadol. They say it does have adverse risk reaction that can lead to respiratory depression and death. So definitely contraindicated, especially in children, but even in adults, you have to be careful with that. And then for a poor metabolizer for codeine is going to result in a lower systemic active metabolite concentration, may result, again, in reduced efficacy here.
All right. So I think we know the answer many times when it comes to Lisa, that she should not be taking codeine or tramadol, and the CPIC guidelines, Dutch Working Group, even the FDA do recommend alternative medications for her. So what are our options? It would really depend on the setting. So if she were in the hospital and she’s going through surgery, then they would probably give her another opioid such as morphine. However, if she’s at home, is just trying to manage that postop pain, then we could try an NSAID for her.
Now last week, we checked out NSAIDs, and that they’re also affected by CYP2C9. So we’re going to have to check her metabolizer status. She’s actually a normal metabolizer for CYP2C9. So any of the NSAIDs would work for her. However, that is not the case for our second patient here. So this is Ben. He’s a 20-year-old Caucasian male, and he just had some dental surgery done. So his doctor did not want to start any opioids. So he gave him an NSAID for pain. And then with dental surgery, NSAIDs worked pretty well because they’re anti-inflammatory. So you have a lot of inflammation after that. So his dentist said, “Okay, you can start on meloxicam 15 milligrams daily for two or three days after surgery.” And he gave him meloxicam because it has a little bit of a longer half-life as well.
However, once Ben took meloxicam, he started having these side effects. His blood pressure was really high. So again, remember, Ben is 20 years old. His blood pressure, normally, runs a little bit on the lower side because he’s also an athlete. So it’s around 100 to 100 over 70. So this is really high for Ben. He also noticed some heart palpitations as well as abdominal pain. Now looking at his PGx information, so here with NSAIDs, we’re focusing on CYP2C9, and he’s actually a poor metabolizer. And it’s also important to note here the type of medication that he’s taking. So he is taking meloxicam, which has a little bit of a longer half-life than ibuprofen and celecoxib, and some of these other medications there.
So in terms of CPIC guidelines or recommendations, there is CPIC guidance here when it comes to these four medications. So celecoxib, flurbiprofen, lornoxicam, or ibuprofen … And lornoxicam, we don’t have it available in the US, but the other three we do. If you are a poor metabolizer, they say to initiate therapy with 25 to 50% of the lowest recommended starting dose. Now this is the case because these medications, as some of you may know, they have a pretty short half-life, so they will be out of your system faster. So that’s why they recommend to even still take them, even if you are a poor metabolizer.
However, Ben was not taking these. His doctor actually recommended meloxicam, again, because of that longer half-life. And he said, “it’s probably going to last a little bit longer. He doesn’t have to take it every six hours.” So for a poor metabolizer, CPIC actually does recommend to choose an alternative therapy that’s not metabolized by CYP2C9 because, again, it is expected for these individuals to have side effects, or you can choose another medication like ibuprofen or Celebrex, but at the reduced dose. And again, it’s because it has a shorter half-life. And then here, for completeness, I’ve also included piroxicam and tenoxicam. They have even a longer half-life than meloxicam. So again, for a poor metabolizer, even for an intermediate metabolizer with an activity score of one, CPIC recommends to have an alternative therapy.
Now the FDA also has some guidance when it comes to these, mainly for a poor metabolizer. So for Celebrex or celecoxib, the FDA says results in higher systemic concentration. So we would reduce the starting dose to 50% of the lowest recommended dose. When it comes to flurbiprofen, meloxicam, and piroxicam, they also say it results in higher concentration and to use a reduced dosage. However, there isn’t any particular dose recommendations there. And then for ibuprofen, again, results in higher systemic concentration, but doesn’t really have any recommendation in terms of any dose adjustments.
So going back to going back to our patient case again … So again, here, as a reminder, Ben took meloxicam for his dental procedure. He had really bad side effects from it. Turns out he’s a CYP2D6 poor metabolizer. CPIC guidelines do recommend, again, four medications there. So Celebrex, flurbiprofen, lornoxicam, and ibuprofen. You can still take them, but you need to initiate therapy with 25 to 50% of the lowest recommended starting dose. And then for the other three there, which Ben was taking meloxicam, meloxicam, piroxicam, and tenoxicam, to avoid them completely.
So what is our plan? So we have a couple of options here. Could try ibuprofen at a lower dose, maybe 25, 50% dose, or if you don’t want to risk it, you don’t want a medication that has anything to do with CYP2C9, then we could also actually try naproxen because it’s not affected by CYP2C9 nine at all. Those are our options there.
All right. We are nearing the end here. So thank you so much for listening to this presentation again, and here are my references. What questions do you have for me? Feel free to type them in the chat or the Q&A portion. Then if you can’t think of any questions right now, as always, here’s my email address. Feel free to email me any time.
So Amy, for patient two, it’s actually CYP2C9. Thank you for pointing that out. CJ has a question for patient one. Would hydrocodone be an appropriate choice for short-term pain? CJ, yes. Hydrocodone could be an appropriate choice just because there isn’t as much evidence out there to suggest that patients have had side effects from it. However, it is metabolized by CYP2D6 a little bit as well. So it really will depend on the comfort of the clinician, whether they would want a medication that’s not affected by that at all, or they would be okay with trying hydrocodone. But great question.
Interested in registering for PGx Clinical Pearls?
Every Thursday at 3:30pm Central Time
https://us02web.zoom.us/webinar/register/WN_Xmg9jxiASRmA2wAeUo3YeQ
For any questions, you can email us at [email protected]
RxGenomix was created to help healthcare providers realize the potential of pharmacogenomics (PGx), giving them the power to tailor treatment to the individual like never before. Our weekly webinar series – PGx Clinical Pearls – takes a closer look at topics related to applying PGx to patient care by using an individual’s genetic profile for personalized prescribing.
