Hello everyone. Good afternoon. Thank you for joining me again today. For those of you that don’t know me, my name is Dr. Ina Liko and I’m the Director of Clinical Pharmacogenomics Operations at RxGenomix. Today we’re going to be continuing on with our theme of pain medications for this month as well. Actually I have the same case study that we went over last week, but didn’t have time to finish that patient. In terms of the agenda, I will start off with that patient case again, and then look to see why that patient, the medication were not working for him. Maybe we’ll find the culprit today.
Then, I will also have an overview of CYP2D6. For those of us who have attended the webinars in the past, you have seen this gene a lot, but that’s because it is an important gene. It does metabolize about 25% of all available commercial medications out there. For those of you that are new, this will be really important for you to know moving forward. We’ll see if there are any guidelines for that specific drug-gene interaction, and then move on to see if there’s any FDA guidance, and then come back to this patient case to see how we can solve this case.
All right. So, the same patient as we had last week. Again, as a reminder here, this is JR. He’s a 60 year old Caucasian male who actually underwent knee surgery. In terms of his past medical history, he doesn’t have a lot of it. He just has depression, but other than that he didn’t really have any other issues until he actually fell and broke his hip, and then he now went to the hospital to have that surgery. That’s when the doctor started him on codeine. They started him on codeine to control the pain when he was in the hospital. He had 60 mg every 4-6 hours. However, his pain was not at all relieved in the hospital. He experiences or reports pain, 9/10 pain score.
Then post discharge, he was sent home with tramadol 100 mg every four to six hours. Again, to control his pain. He actually comes back to the pain clinic the very next day and says that his pain is still not controlled. He’s still reporting pain 9/10 pain score.
Definitely not an ideal situation for this patient. In terms of his other medications, he’s just taking Paroxetine for his depression and that’s controlled. So, his depression is controlled. We’ll mainly be focusing today on figuring out why these medications are not working for him for pain. Because as many of you know, these are very strong medications that do help some patients to control their pain.
Fortunately, he did have a pharmacogenetic test done, and these are his results. The main one we’re going to focus on today, the main gene will be CYP2D6. Last time we talked about OPRM1 and COMT. We saw that for him, that OPRM1 might have also contributed a little bit in him not responding to codeine and tramadol there. The research for COMT is still not very strong as of now. More research is being done when it comes to those drugs and interactions, with pain medications and COMT.
So today, let’s see how CYP2D6 is related to the opioids. For starters here, before we dive into the particular medications. Just as an introduction again, and a review really, of CYP2D6. So CYP2D6, fun fact, is the only inducible enzyme in the (CYP) P450 family. It also makes up about 10% of the CYP content in the liver, and more importantly for us, that’s why we keep seeing it along a lot of different drug classes, is because it does metabolize up to 25% of all clinically available medications.
Now, CYP2D6 is also very highly polymorphic. It does have a lot of different variations and different types of variations. Some of these variations which are the most common are what we call single nucleotide polymorphisms or SNPs, but with CYP2D6, there are also insertions and deletions. There’s duplications as well as multiplications. Then to complicate things even more, there’s also these hybrid genes that are actually composed of CYP2D6 and CYP2D7. So all of these genetic variants, they can alter the pharmacokinetics of the enzyme. This can lead to increased function in those that are carrying additional functional genes or to decreased function or no function with gene deletion here. Some of these don’t have any functional consequences at all.
We see four different types of genetically mediated CYP2D6 phenotypes. There is the ultra rapid metabolizer where we would expect a poor drug response because in this case, we would expect the patient to really metabolize the medication really, really fast. It’s out of their system really fast unless they’re taking a prodrug, which actually, codeine and tramadol are prodrugs. They need to be activated by CYP2D6 to morphine. So if a patient is an auto rapid metabolizer of CYP2D6, and they’re taking a prodrug, then they’re actually converting codeine to morphine at a very fast rate. So, they have a higher concentration of morphine in their system, and this may actually cause them to have side effects. Kind of the opposite effect happens with the prodrugs here. When we think about how they affect us in terms of… Unless, if we don’t have a prodrug, we would expect that the poor drug response for rapid metabolizers, but that’s not the case for prodrugs. If you have any questions about this concept, feel free to put your questions in the chat or the Q&A portion, and then I’ll address them at the end.
Now, when it comes to intermediate on poor metabolizers, we actually see as the opposite of an rapid metabolizer, where we’ll see that in these cases, we would expect for some of these patients to have more side effects. Because the medication, it’s not being metabolized as fast. So in that case, some of it is left over. You have higher concentration. The medication is in the system for a lot longer than it should be there. Then again, in the case of a prodrug such as codeine and tramadol, we actually would expect that these patients would not respond to medications because they don’t have enough of that enzyme to actually activate codeine, or tramadol, or other medications that are prodrugs to the active metabolite. Which in the case of codeine and tramadol, is morphine. Right. Now that we have idea about this concept of prodrugs and how CYP2D6 particularly may affect tramadol and codeine, let’s see what activity score or what phenotype our patient really is.
With CYP2D6, in order to calculate a phenotype, we actually need to calculate an activity score. So, activity score is calculated based on the patient’s genotype. For this patient, as a reminder here, the genotype is *5/*6. The activity value of *5 is zero, so it’s a no function allele. The activity value of *6 is also zero. In order to calculate the score, we actually will just add these two up. So 0+0, the activity score will be zero, and this does correspond to actually a phenotype of a poor metabolizer. So, keep this in mind as we move on through some of these guidelines when it comes to codeine, tramadol, and CYP2D6 for metabolizers.
Here, I just wanted to point out how codeine is actually metabolized. It is metabolized mainly by CYP2D6, that’s why it has a star there, into morphine. So again, we just found out that our patient is a poor metabolizer of CYP2D6. So in that case, they’re just not converting codeine to morphine at a faster rate. So, that could be one of the reasons why they’re actually not responding to codeine, why it’s not controlling their pain at all.
Now, may also wonder how common this variation is. Here, just wanted to point out that in Americans, in about 25% of the population, they’re either intermediate metabolizers or poor metabolizers. We have about 5% who are ultra rapid metabolizers. So overall, about 30% of the population does have a variation in CYP2D6 that can affect drug response.
Now, another important concept that I would like to review here, and particularly important for this patient because he’s actually taking one of these drugs, is this concept of phenoconversion. I know those of you that have attended our webinars in the past have heard about this concept, but I always want to bring it up to review for individuals that haven’t heard this before. Also, because this patient was actually taking one of these medications. Phenoconversion, it’s a mismatch between the individual’s genotype-based prediction of drug metabolism and the true capacity to metabolize drugs due to non-genetic factors. For example, changes due to drugs inhibiting or inducing metabolizing enzymes, they can severely impact an individual’s ability to respond to a medication. So, if a patient is a normal metabolizer per their genotype, they may actually act as an intermediate or a poor metabolizer due to pheno-conversion.
For CYP2D6 particularly, this occurs in patients who take medications that are strong CYP2D6 inhibitors. As you may recall, our patient is taking one of these medications. He’s actually taking Paroxetine. Because of that, he could actually have that phenoconversion happen to him as well. However, typically we already found out that he’s a poor metabolizer of CYP2D6. So, this phenoconversion would not affect him as much because he already has very diminished activity or function of the simplistic enzyme. So for him, even though he is taking Paroxetine, it wouldn’t necessarily affect or interact with the medications with codeine or tramadol. But if he was an ultra-rapid metabolizer, for example, or even a normal metabolizer, just because he was taking Paroxetine, he may actually act as an intermediate or poor metabolizer.
In that case, if we only looked at his genetics, we would not have been able to figure out why he’s not responding to this medication because per his genetics, he should actually responding to it very well. Also, this is important to remind us that when we look at a pharmacogenetics, to always keep the whole patient in mind, not just their genetic profile and how it relates to their medications. But, also looking at other medications that they’re taking and their medical history, what they’ve tried in the past. In this case, I wanted to remind us that it is very important to look at drug-drug interactions as well.
Now moving on a little bit, switching gears in terms of the guidelines. Our patient was a CYP2D6 poor metabolizer and CPIC guidelines, they have guidance for three drugs there. So codeine, hydrocodone, and tramadol. Mainly focusing on codeine and tramadol, because that’s what our patient tried. CPIC guidelines, they recommend to avoid codeine use because of the possibility of diminished analgesia. Again, this is because we’re not activating codeine to its active metabolite, which is morphine. Similarly, Tramadol has a very similar mechanism of action. So similarly with tramadol, CPIC recommends to avoid tramadol as well.
Now for complete NCR, I’ll go over ultra-rapid metabolizers and intermediate metabolizers. For ultra-rapid metabolizer, we have the opposite issue here because we’re converting codeine and tramadol to morphine at a very fast rate. In this case, we would expect potential for serious toxicity and a lot of side effects. So again, the guideline is similar in terms of avoiding these two, and then maybe choosing something that’s not affected by CYP2D6 as much. Hydrocodone could actually be another alternative here. For intermediate metabolizers, CPIC guidelines recommend to use label recommended age specific or weight specific dosing. Then if no response and opioid use is warranted, to consider non-codeine, as well as non-tramadol opioids.
Now, the Dutch Working Group also has some guidance when it comes to these medications, particularly codeine and tramadol, very similar guidance to CPIC. However, they do give a couple of alternatives for tramadol. For ultra-rapid metabolizer they have specified, for doses that are over 20 mg every six hours in adults, and over 10 mg every six hours in children. They say that codeine is contraindicated, and it would be advised to choose an alternative therapy. For tramadol, they also say you can choose an alternative therapy. However, if you don’t have an alternative therapy, then to use about 40% of the standard dose. So, this is a 60% dose reduction.
For intermediate metabolizers, they say to be alert of reduced effectiveness and try increasing the dose if the medication is not effective, but no particular dosing guidance there. Then similarly, with the poor, metabolizers the alert of reduced effectiveness when it comes to tramadol, and then in case of inadequate effectiveness, they do recommend to choose an alternative. For codeine, if you’re a poor metabolizer, they recommend to choose an alternative. So, the difference here between CPIC the Dutch Working Group is really for tramadol, the Dutch Working Group does have some alternative options if this medication it is needed.
Now, the FDA also has some language when it comes to codeine and tramadol, mainly for ultra-rapid metabolizers and poor metabolizers. You’ll see there that the language, particularly for an ultra-rapid metabolizer, for codeine and tramadol is a little bit stronger. For codeine, said it results in higher systemic active metabolite concentration, as well as higher adverse reaction risk. It is life threatening, respiratory depression and death, and codeine is actually contraindicated in children that are under 12 years of age. Again, because of that very high conversion of codeine to morphine in an ultra-rapid metabolizer. Similar guidance here for tramadol, it is contraindicated in children under 12 and in adolescence, because usually children are given this after they have tonsillectomy or even a duodenectomy.
Also in breastfeeding, it’s not recommended during this treatment. That’s because there were a couple of incidents where mothers that were taking codeine, actually codeine was transmitted into their breast milk and their infants died because that they had a very high conversion of codeine to morphine in the breast milk, and it was a very high dose for the infant. So, that’s why the FDA actually has a contraindication there. When it comes to a poor metabolizer, the guidance is more related to codeine. It will result in lower systemic active metabolite concentration and may result in reduced efficacy. So, they don’t necessarily have any particular dosing recommendations there.
All right. Now, let’s go back to our patient case. Just as a reminder, his pain was not controlled. He had really, really high pain here, 9/10. Codeine and tramadol, they failed to control his pain. We found out that he’s a poor metabolizer. Then in terms of the guidelines, CPIC has to avoid coding and tramadol due to diminished analgesia. Similarly, the Dutch Working Group also states to choose an alternative whenever possible, and the FDA also states that this may result in reduce the efficacy. We do have different resources here that are agreeing on a similar conclusion that codeine and tramadol may not be the best because this patient will have diminished analgesia, and if it’s possible, to choose an alternative medication.
Now the plan here, you can choose couple different options. This is what I was thinking about. So first of all, to discontinue tramadol for him because it’s clearly not working, and then consider starting an NSAID to control his pain. Now, that tramadol is a little bit stronger than that, but for him, it’s tramadol is just not working at all. So, it’s not a matter of whether he needs a stronger opioid. It’s just because it wasn’t working due to his genetics and metabolizer status. So starting him off with an NSAID might be a good idea, and then if it’s not controlled, we can move to another opioid. Now, in terms of what NSAID to start him on. They are also affected by genetics, so we will continue this case next week to find out what NSAID would be best for him.
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