Episode 7: Surgical Pain Management, Mental Health Medications, and Personalized Medicine

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Today’s episode titled “Surgical Pain Management, Mental Health Medications, and Personalized Medicine” features Dr. Matthew Philp, MD, a colorectal surgeon and associate professor at Temple University, Lewis Katz School of Medicine and Dr. Emily Cicali, PharmD, a clinical associate professor in the Department of Pharmacotherapy and Translational Research at the University of Florida. Dr. Philp serves on the Steering Committee of the PENNJ-SOS collaborative program.

Resources shared in this episode:

Host & Guests:

  • Host: Dr. Matthew Philp, MD; Temple Health
  • Guest: Dr. Emily Cicali, PharmD; University of Florida

Transcript:

Dr. Matt Philp:
­­Welcome everyone. My name is Matthew Philp. I’m currently an associate professor of clinical surgery at Temple University, Lewis Katz School of Medicine in Philadelphia, Pennsylvania. I’ve been a practicing surgeon for 13 years. I did my residency training here at the Temple University Hospital, where I practice, and fellowship training at Lehigh Valley Hospital in colon rectal surgery, which is my subspecialty. I’m currently the President of the Pennsylvania NSQIP Consortium. NSQIP is the National Surgical Quality Improvement Program, run by the American College of Surgeons. I currently serve on the steering committee, as well for the Pennsylvania New Jersey Surgical Opioid Stewardship, or PENNJ-SOS, which is a collaborative group of us, within our consortium, that are looking specifically at surgical opioid use, and trying to improve patient outcomes around that medication class.

Today, I’m happy to welcome Emily Cicali. Emily is a professor at the University of Florida’s department of Pharmacotherapy and Translational Research. She’s a director of the University of Florida Health Pharmacogenomics Clinical Consultation Service. She has her doctorate in pharmacy, which she earned right here in Philadelphia, at the University of Sciences. A little bit of a welcome home for you, Emily. Has dedicated her career to medication safety, specifically focusing on clinical pharmacokinetics, phenoconversion and pharmacogenomics implementation, which I’m interested to hear a little bit more about. I want to welcome you, Emily, and please add anything about yourself that you want to add.

Dr. Emily Cicali:
Thank you so much for that great introduction. I’m so happy to be here to talk to you today, to talk about this very important topic. I did want to clarify that University of FL Health Pharmacogenomics clinical consultation service is called MyRx and is led by the college of pharmacy.

Dr. Matt Philp:
Okay. Emily, yeah, we’re going to have a little conversation about medication usage, and I know you’re an expert on pharmacogenetics, so some of this information might be a little bit beyond the patient population comprehension, but we’re going to talk about some things that are specific for clinicians and prescribing, and then get a little bit about how these things can impact patient care, and some impact on the patients, as well. We’re going to do a little bit of both here. Might get a little technical, we’re going to try to explain things the best we can, but should be a good conversation.

Dr. Emily Cicali:
Sounds great.

Dr. Matt Philp:
A little bit of a background, just for our listeners. Several years ago, the use of opiate medications was becoming a hot topic issue, and we had a big collaborative discussion about how we could look at that problem, talk about it, and maybe make some changes to practice, and really kind of grew a very large project that included patient education, education for our surgical colleagues, as well as data collection about the use of opiate medications.

A number of interesting findings, but one of the more recent ones that we published last year, in the Journal of the American College of Surgeons, was that we found patients that were on both opioids and benzodiazepines both had increased risk of surgical complications, which you would expect, but when we looked at the subset of patients that had both of those medications, had over two and a half times more likelihood of having serious comorbidities. What’s the landscape currently for those? How often are they being prescribed? Any other insights you have on that?

Dr. Emily Cicali:
Yes, co-prescribing these two medication classes together certainly can have significant risk for the patient, and you want to make sure that your patient is going to have the safest medications prescribed to them. When you’re thinking about these two classes of medications, specifically these benzodiazepines and our opioid medications, there’s going to be respiratory depression, decreased… slowing the breathing, and that could be potentially very dangerous for the patient. There’s also high relevance and high prescribing of antidepressants in patients, typically with chronic pain, but especially in acute pain as well, over… I think it’s over 30 million patients currently have a prescription for an antidepressant right now. When we’re thinking about certain antidepressants, those can actually impact how well the opioid medication, for post-surgical pain, will work.

Dr. Matt Philp:
It was specifically benzodiazepines in our publication, but we can certainly talk about antidepressants too. We haven’t published that data yet. We’re still collecting it actively.

Can you give me some more examples of that? Because that’s an interesting concept, I think titrating our pain control regimen, for our patients is important. Not everyone experiences pain the same way. What antidepressants should we be looking out for, as surgeons, that may impact our patient’s acute post pain, after surgery?

Dr. Emily Cicali:
Absolutely. Great question, so really when you have a patient that you’re evaluating them for postoperative pain, you’re probably not going to be touching their antidepressants, because as you know, it takes patients a long time to become stable and controlled for their depression, or mood symptoms, anxiety, as well. CYP2D6 metabolizes about 25% of all medications, opioid medications being part of that class, and CYP2D6 is highly polymorphic—that just means that a lot of people carry different genetic variations in this gene, which can make their drug metabolizing enzyme different than the majority of the population. About 15% of the population has reduced CYP2D6 enzyme activity.

Specifically, we’re looking out for bupropion, duloxetine, fluoxetine, and paroxetine. Those are four different antidepressants that inhibit CYP2D6, to varying strengths. And if you have a patient that comes in on these medications, they’re likely controlled, so you’re not going to want to touch their controlled medication for just an acute regimen of postoperative pain. You’re really worrying about the impact that that’s going to have on those pain medications.

Certain opioids, codeine, tramadol, hydrocodone and potentially oxycodone, those all have to be activated in the body by the drug metabolizing enzyme known as CYP2D6. When you have these antidepressant medications on board, the opioid medication isn’t going to work. You’re potentially not going to get the analgesic relief that you’re expecting, when prescribing these medications. Knowing that the patient is on these inhibitors, you can either more closely monitor them, and either still try that opioid, but maybe check in with them sooner, or prescribe an alternative. For example, hydrocodone as you know, is metabolized to hydromorphone by that CYP2D6 enzyme. So, you could just go right ahead and prescribe the more potent hydromorphone, that you would be more confident that the patient would have relief from.

Dr. Matt Philp:
And do most hospital EMR systems have drug interaction checking for these? Because I’m not sure if I’ve ever seen this as a drug… I mean, I get a number of alerts, and as physicians we get a lot of alerts, and there’s a lot of talk about how many alerts are we getting, and how do we manage them. Is this something that’s commonly done in most EMRs, and what should we be doing when we get that alert? What should we be thinking about?

Dr. Emily Cicali:
Absolutely, so there are, for certain of these combinations, there are alerts in place. you will see, “Can diminish the effect of tramadol,” for example. It is there specifically, with bupropion, and fluoxetine, and tramadol. It’s not as strong there for oxycodone, which does make sense, because oxycodone does have some analgesic effect, as the parent compound itself. It’s not as potentially a severe interaction with oxycodone, as compared with the other medications. Then with hydrocodone, it’s there, but I feel like it gets buried oftentimes, and it might not be as clear to the clinician or to the pharmacist when they’re seeing those drug interactions.

Dr. Matt Philp:
Gotcha. Are there any other toxic side effects of the tramadols and things, that are not converted, as patients… are there other side effects, that can occur from those?

Dr. Emily Cicali:
Yeah, absolutely, so there’s also risk of serotonin syndrome. You would want to look… have your patient be monitoring for those effects. Serotonin syndrome or serotonin toxicity is more rare, but it could happen.

Dr. Matt Philp:
Gotcha, and someone with serotonin syndrome could certainly have a range of complications; diarrhea, flushing, abdominal pain, discomfort that would show up in surgical complication type pictures.

Dr. Emily Cicali:
Exactly.

Dr. Matt Philp:
Are the doses of the antidepressant medications, is there a direct correlation with how much conversion enzyme suppression there is, so patients on the higher doses are more likely to have this, or is it not dose dependent?

Dr. Emily Cicali:
That’s a great question. To the best of our knowledge, it’s not really dose dependent, at this time, and that’s because they’re non-competitive inhibitors. No matter what the dose is, they’re going to come in and allosterically bind to that drug metabolizing enzyme, and deem it non-functional. Regardless of that dose, it’s thought to have a very similar effect. Duloxetine is a moderate inhibitor, whereas paroxetine, fluoxetine, and bupropion are strong inhibitors. So, it’s possible with duloxetine being more of that moderate inhibitor that could be more dose-dependent, but we just don’t have a lot of information quite yet, to know what that dose is, to truly have that same impact.

Dr. Matt Philp:
Gotcha, so that’s a great comment. Maybe I’ll transition a little bit. Tell us more about what pharmacogenomics is because I’m not sure I’m fully educated on that, although I have an inkling on what you just said. Are we now in an era where we’re going to be looking at specific patients’ genetic factors, and their enzyme supply and transition, and how we prescribe medications for them?

Dr. Emily Cicali:
Absolutely. It’s definitely a growing field. It’s been around for over a decade now, but it’s still unfortunately not the standard of care. But there are different guidelines available, to help guide drug dosing, when you have this information available. Pharmacogenetic testing is a simple cheek swab or blood test that patients can get done, and it looks at just the small section of your DNA to know how you respond to certain medications. It’s really only telling us about those drug metabolizing enzymes, or in some cases drug transporters and what that enzyme activity is.

Actually 9 out of 10 individuals might have a genetic variation that changes their enzyme level. And so, when you have the genetic information, you would know if someone has either normal drug metabolizing enzyme, or reduced, or even increased, and if you have increased enzyme activity, you’re going to have increased metabolism in the body, and if you have reduced enzyme activity, you’re going to have reduced metabolism in the body.

And so, with our opioid example, these are medications that have to be activated in the liver, so individuals who are ultra-rapid metabolizers, or have a genetic variation that makes their body have more of that enzyme present, they’re going to convert to more of that active metabolite, and then potentially be at risk for side effects, respiratory depression, and some other serious events.

This is certainly can be more of a complicated topic at times, and having the pharmacist involved in care can be hugely beneficial, to both the patient and the clinician, or surgeon. There are different services out there, or pharmacists like clinics, that provide consultations to help interpret pharmacogenetic results, especially in context of drug interactions, that can be leveraged by individuals. There are certain ones in specific states. We have one in Florida called MyRx. University of Penn has a pharmacist led pharmacogenetics clinic, as well. If you need additional help with interpreting these results, or with these drug interactions, and you’re not necessarily sure how to apply them.

Dr. Matt Philp:
Emily, who gets referred to these clinics? Are they coming from previous problems with medications? I’m just curious about.

Dr. Emily Cicali:
Yeah, it depends. At University of Florida, actually all of our orthopedic surgeons will get patients tested they’ll do a blood test, or a cheek swab, and then get that information ahead of surgery, and then we provide a consult note for them, so that way the information is available, by the time that they go to prescribe the medications. We do the test at the initial appointment, when surgery is being decided. Then at the pre-op appointment is when the results are back, and then they can actually use that information to prescribe medication.

Dr. Matt Philp:
Yeah, it’s a great point, because in our data set, patients that were orthopedic patients, or neurosurgical spine patients seem to have… they had obviously higher the highest rates of prescribed narcotics, and they have a little bit more complex pain control issues postoperatively, with their joint procedures, and spine procedures. It seems like a great use of that information, to have individualized, personalized medicine, for those patients.

Dr. Emily Cicali:
Absolutely, and we just wrapped up a multi-center trial that looked at acute pain, and major surgeries that resulted in, at 10 days postoperatively, the most pain, and trying to see if we can reduce that amount of pain. That was an IGNITE-II trial. It’s called ADOPT Pharmacogenomics, and those results should be coming out in the near future.

Dr. Matt Philp:
Yeah, it’s a great example of personalized medicine, and information that we never had. I think I see it as a clinician, to me, I want to get your opinion on this, we have pain postoperatively for patients, or acute pain generally, is very different among patients. We’ll have patients that have very large incisions and have almost no pain, and patients with very small incisions will really experience tremendous amounts of pain. The medications that we have to give them, just talking about opioid medications, can vary dramatically. Some patients need very high doses, some need very small amounts. Does that explain a lot of that variation difference, and it’s something that in the future that maybe we’ll have some more information on, and be able to use that to appropriately prescribe opioid medications?

Dr. Emily Cicali:
Exactly. You hit the nail on the head there, so it certainly can tell us those patients that might not be responding to the specific opioid medication, and it is about… 2% to 3% of the population is ultra-rapid metabolizers, and about 15% of the population has that reduced enzyme activity. Really about 15% of your population might not respond to those medications. Even increasing that dose isn’t going to overcome that absence of enzyme activity. Interestingly, when you’re thinking about the drug interaction piece, or some of those antidepressants that we were just talking about, that 15% of the population actually jumps up to about 20% to 30% of the population. Even if you don’t have the genetic information, just knowing their concomitant medications can help you still apply these same recommendations.

And, I think the recognizability of these recommendations, going back to having clinicians know about these drug interactions, yes, it’s in the drug interaction databases, but a lot of the information comes from really more within the pharmacogenetic space, and some of these pharmacogenomic guidelines, that then you can apply these recommendations.

Dr. Matt Philp:
Awesome. Yeah, it’s going to be more complicated it seems like, but I mean, hoping the tools that we have will enable us to use that information a bit more effectively.

I want to go back for a second. Oxycodone is probably one of the more commonly prescribed narcotics that I use acutely, but you talked a little bit about tramadol. I want to just ask your opinion on tramadol, because a lot of times I’ll use that, as a clinician, as a lower strength opioid medication. But there are issues with that, as you mentioned before. What other thoughts or concerns should we think about, for prescribing tramadol for patients, and what do we need to worry about that medication?

Dr. Emily Cicali:
I think tramadol is a great drug, to be honest. I think that’s a great go-to, and I think that if you know that someone is able to metabolize opioids, then that is really a good go-to, just to overall reduce the overall morphine milligram equivalence. There’s actually some data out there that looking at pharmacogenetic guided, versus usual care, can actually reduce the amount of MME requirements for those patients. MME is morphine milligram equivalents, and this is just a metric used, where we can compare the opioid medications, and different potencies. A lot of our initial go-to opioid medications tend to have a lower MME, and those are the ones that are metabolized by CYP2D6.

So, really I think the consideration with tramadol mainly, is can they activate the drug, because that does depend on CYP2D6, and then thinking about really just any other serotonin medications that they might be on, to accumulate that serotonin and avoid the risk of serotonin syndrome.

Dr. Matt Philp:
Gotcha. We were talking about antidepressants, but I led into it a little bit with benzodiazepines. Maybe we can talk a little bit about benzodiazepines use perioperatively. If we’re seeing a patient, as a surgeon in the clinic preoperatively, and we see them on the class of benzodiazepines, what considerations should we have for perioperative management of these medications, continuation, discontinuation, any role for tapering, or changing from short to long acting, or what concerns do you have as a pharmacist, for someone undergoing a surgical procedure, that’s on benzodiazepines?

Dr. Emily Cicali:
Great question. I think benzodiazepines, as compared to antidepressants, are a little bit easier to discontinue, in the short-term. You would want to taper those off. You wouldn’t want to, cold turkey, stop those medications. But I would also be considering the age of the patient. If they’re an older patient, then it might be more difficult to come off that medication, but it’s also riskier for an older patient to be on concomitant benzodiazepines and our opioid medications.

Dr. Matt Philp:
Yeah. Our data actually showed about 10% of our patients, in our over 4,000 patient data patient cohort, 10% were on benzodiazepines, which is… I was a little shocked personally, but I guess these medications are common.

Dr. Emily Cicali:
Yes, they are very common, and they’re traditionally more meant for the short-term use. But unfortunately they end up staying on medication lists, and patients continue to use them. They do actually lose effectiveness over time, but patients might not perceive that as the case, so they may be more resistant to coming off that medication. But they certainly come with a lot of risk. And, I think surgery is a really great time to evaluate medications. What can we change, because of the additional medications that need to be prescribed, at that time.

So, you can make it very patient-specific, but if you have a few weeks, so evaluating at that pre-op appointment, is a great time to try and come down on benzodiazepines. Even if you can get it, at least a lower dose, this is something that is more of an additive effect with the interaction, so a lower dose is better than that higher dose.

Dr. Matt Philp:
Gotcha. Great information. I want to transition a little bit and ask you a little bit about the importance of medication reconciliation. I’m sure you’re well aware, one of the National Patient Safety Goals is medication safety, and reconciliation is important. I think it’s something we struggle with, a little bit, as clinicians sometimes. What thoughts do you have, as an expert in pharmacy, about what we should be doing and looking at as clinicians, especially in the perioperative patient? If you have any specific thoughts about med recs, best practices around that, and how we should be doing that better, and more efficiently with our patients?

Dr. Emily Cicali:
Absolutely, so if you have access to dispense history, that’s always a great place to start. Usually, dispense history information will be anything that the patient picked up from the pharmacy, was ran through their insurance.  that’s a great way to start with a starting medication list, and really just ensuring that you’re confirming each medication with the patient, or if you have the time, ideally having the patient bring in their pill bottles, “What are you currently taking?” That way you can actually verify, with the patient, each medication.

I think definitely an issue with medical records is oftentimes medications stay on the medication list for quite some time. I see that too often where patients report, I’m no longer taking this medication, but then it continues to be on the med list. Continuing… I think really just like best practices, every touch point, to do a med rec, evaluate that med list, and if you’re confident in that med list that you have, then you would be confident on what the patient is actually taking.

Dr. Matt Philp:
Yeah, it’s a great point. I mean, something I think unfortunately, a lot of my surgical colleagues tend to gloss over. I see it all the time. It says flag for removal in the patient list, and it’s just sitting there forever, because no one wants to take ownership of it. But really anybody can do that. It’s just ask the patient, “Are you still taking X, Y or Z,” and remove it.

Dr. Emily Cicali:
Absolutely. Yeah, so that would be my advice is, don’t worry about taking ownership. I mean, we’re all on the same team for knowing what the patient is taking, even if it’s a medication prescribed by another doctor. I know that there’s oftentimes, like you mentioned, not wanting to take that ownership of that medication. But if the patient’s not taking it, it’s better to have more accurate information on their med list.

Dr. Matt Philp:
Yeah. Is there any role for, or any improvement with compliance for these things, when there’s pharmacy specific clinics? I mean, that’s something we’ve discussed here a little bit, and there’s a cost issue with that, and having a pharmacist spend their time doing that, as opposed to other busy things that you have to do. Is there any good data on the role of pharmacist-directed clinics for medication management reconciliation?

Dr. Emily Cicali:
Yeah, great question. I’m not familiar with the exact data, but I know that there’s lot of different models out there, where hospitals will leverage pharmacy technicians, in addition to the pharmacist. That has been very successful because you have someone who is familiar with the medications and will take the time to ensure that the medication list is accurate. But I think nurses can also do the med rec. That’s often the case, when you’re roomed for that appointment, going over the medication list, oftentimes asking just were there any changes, is a good question to ask. But if you go through the medication list one by one, you tend to find out more information from the patient, whether they’re truly taking it, or not taking it, or taking it differently.

Dr. Matt Philp:
Great. Artificial intelligence is something that people have been talking about for the last, I don’t know, year or so, and it’s just people throw the word out there. But I’ve heard it in a fair amount in the pharmacy space. I was just wondering if you have any insight or experience, in terms of how we may use AI for med rec checking, interaction checking, as a way to again hopefully catch medication errors, or conflicts, or problems? Any experience or insight you have on where AI is going to be going in pharmacy space?

Dr. Emily Cicali:
Yeah, definitely a hot topic for sure. My experience, so far, has been thinking about AI as more of a teaching tool, and how to help initiate patient cases that give you a nice starting point, for teaching purposes. I think there’s a lot of potential, within healthcare, with caution. I think there’s potential for AI to help with consult notes, or drug interactions. I’ve heard of people using AI to help develop patient-friendly information—I think that could be a true benefit. My only caution is just not to use it at face value, and just to make sure that it gets double checked and reviewed, to make sure you’re getting accurate information out there. I’ve heard of AI specifics that are associated with different health systems, so that way it can be within protected PHI, as well. Definitely a consideration with using AI, and with PHI, and interested to see where that goes in the future.

Dr. Matt Philp:
Yeah, for sure. One of the goals of the PENNJ-SOS Consortium was to build education material and resources, for both clinicians, but patients, as well. I certainly encourage people to go check out our website, and see previous podcasts, and education resources we’ve come up with. Do you have any other thoughts about educational materials for both providers or patients, in terms of medication management, and the perioperative periods, things that you think are useful, or helpful for people?

Dr. Emily Cicali:
Yeah, definitely. For patients, there’s definitely a lot less, as you know. There’s Medline Plus, which is a nice resource for just reviewing specific information about drugs. Certainly the package labeled information that they get once they pick up the medication is also a great resource. There’s less in those resources about the specific drug interactions. So, I do think that the motivated patients, who are interested to look at more of the drug interactions, are going to have to defer to their pharmacist, their surgeon, their primary care physician, to ask questions. I would just really encourage patients to bring this up, “I’m on this medication. Will this interact?” Obviously, the healthcare professionals are checking that information, but, if the patient brings it up, that also provides a nice double check. But there’s definitely less patient-friendly resources out there.

As far as physician-facing resources, specifically for drug interactions, and some of what I was calling the phenoconversion, so that drug interaction on the CYP2D6 enzyme, there are a few different resources out there. There’s something called Sequence2Script. It uses genetic information as what you put into the system, but it helps to output recommendations, based on genetics. But you can also add in drug interactions. There’s the PROP Calculator by University of Florida, that tells you what clinical phenotype you should be using when applying, or looking for specific recommendations, but it doesn’t give you the actual recommendations. You would have to then go to the guideline to obtain those.

PharmGKB is another really great resource. Again, all very pharmacogenomics focused, because that is my area, but it does have that information for drug interactions, and it’s just a really great resource for finding out more information about the metabolism of the medications. Then the Flockhart Table, so another resource, along with FDA, have different tables that will actually list out drugs that interact with these drug metabolizing enzymes. Helps you to be aware of what medications you might want to look out for. Then when you see them in the drug interaction checkers, or the pop-up alerts, you might have a better idea of what that is exactly saying, or reaching out to pharmacists as well.

Dr. Matt Philp:
Awesome. Yeah, maybe we can get some of those resources up on our website, the links, because I think… yeah, that would be some interesting information for practitioners to check out, as well.

Dr. Emily Cicali:
Absolutely.

Dr. Matt Philp:
Emily, thank you so much. I think this was a great conversation. I learned a lot about pharmacogenomics. I’m looking forward to learning more about it, in the future, and I appreciate your thought and insight into how we manage our patients’ medications in the perioperative period. Thanks again for joining us.

Dr. Emily Cicali:
Thanks so much for having me. It’s been a pleasure.

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