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Join Amy Baxter, a clinical associate professor of emergency medicine and CEO of Pain Care Labs, to unravel the complexities of this critical topic. We’ll explore the interconnectedness of pain and reward areas in the brain, genetic factors influencing addiction susceptibility, and the distinct feeling of euphoria in the context of opioids. Discover how the brain responds to prolonged opioid exposure and how liver metabolism genes play a role. Join us to gain valuable insights into the science behind addiction and treatment approaches for opioid use disorder.

Amy Baxter is a clinical associate professor of emergency medicine at Augusta University, federally funded for neuromodulation research to reduce needle pain, multimodal low back pain, and opioid reduction. After attending Yale University and Emory Medical School, she completed her residency and a child maltreatment fellowship at Cincinnati Children’s Hospital Medical Center, an emergency pediatrics fellowship in Norfolk, Virginia, and a K30-NIH Clinical Research Certificate at UT Southwestern Medical Center. She is also CEO, Pain Care Labs, and can be reached on Twitter @AmyBaxterMD.

She discusses the KevinMD article, “Misunderstandings about opioid use disorder.”

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Transcript

Kevin Pho: Hi, and welcome to the show. Subscribe at KevinMD.com/podcast, and get CME for this episode by clicking on the CME link in the show notes. Today we welcome back Amy Baxter. She’s a pediatric emergency physician, and she’s the CEO of Pain Care Labs. Today’s KevinMD article is titled “Misunderstandings about opioid use disorder.” Amy, welcome back to the show.

Amy Baxter: It’s great to be back. I’m hoping to become a longtime friend of the pod.

Kevin Pho: Fantastic. And to hear Amy’s story, go to KevinMD.com/podcast, click the search icon in the upper right-hand corner, and search for her previous episodes to hear her story. But today let’s jump right into your most recent KevinMD article, “Misunderstandings about opioid use disorder.” Tell us how this article came together.

Amy Baxter: Well, I had a very good friend from high school who overdosed on heroin when I was in my second year of college, and I was furious with her for two decades, three decades. I didn’t go to her funeral. How could she be such an idiot? And now that I have been working with NIDA, and I’m funded to reduce opioid use by providing alternative methods for pain management, I have learned so much that it just makes me really want to explain to people what we know now. If I’d known it then, I might have been able to keep her from dying, but certainly it would have replaced my anger and disappointment with empathy and understanding.

Kevin Pho: All right, so tell us what you learned.

Amy Baxter: So there are about 10 genes that have now been identified with different neurotransmitter processing. Dopamine is the one that everybody’s going for, to make you feel great. That is the reward. It’s not really novelty; it’s more mastery, it’s more feeling empowered. And so most of the substances that people take modify the dopamine pathway. Now, you’ve got other pathways, serotonin, oxytocin, feeling loved, feeling all these things. Well, it turns out that when people misuse opioids for the first time, there are really distinct differences between people who go on to get opioid use disorder and those who don’t, and all of this has come out in the past five years or so.

It turns out that about 14 percent of people will get an amazing reward sensation from opioids that they often haven’t gotten from anything else. Their dopamine reward systems are deficient. Whether it’s that the dopamine they’re making isn’t striking the mu receptors enough, or that they’re not receiving the dopamine that’s made as well, they are not getting as much of a buzz from normal activities. And so when they take an opioid, they have never felt that great. They have never felt that warm, loved, happy, et cetera. So when people take opioids from medicine cabinets, or their friends’ medicine cabinets, which is where about 60 percent of opioid use disorder starts, that first reaction really is genetically dependent, and it’s very predictive.

In my article, I used the reactions with the highest P values in these studies of people who did and did not develop opioid use disorder, and it’s really stunning how, for example, 96 percent of people who develop OUD feel relaxed and fluid in their movements. I don’t know, how weird is that? But that’s the most predictive, or the most highly correlated. And then the others are things like, I felt loved by everybody, I felt comfortable in my own skin, I felt all these things.

When I was practicing, I had one of the best trauma nurses I’ve ever worked with, who ended up developing opioid use disorder, addicted to fentanyl, stealing it from kids, and it started with a gallbladder. I asked this person later, how on Earth did this happen to one of the best trauma nurses I ever worked with? And he said, “You seem comfortable in your skin, you seem happy, and you know you’re loved. I never felt that until I took that first opioid.”

So all this is to say, first of all, that the family history, which is what we use now, is really a genetic history. The reward is so compelling, so much stronger than any other kind of substance in terms of how it rewards you, that introducing opioids to the opioid-naive is going to carry risk. The other part of it is that my friend was adopted. She was a chain smoker in Kentucky, where I grew up, and I didn’t realize how much overlap there is between stimulation from nicotine and this reward deficiency. So there was that. And if I’d known she was adopted, well, kids are often given up for adoption for a reason. She probably had a family history of this genetic predisposition to substance abuse, and knowing that probably could have warned her, and probably could have warned her parents, and prevented that whole cascade of suffering. If we know that a large number of people are going to respond differently, then we can identify them early. We can say, OK, you responded with euphoria to this first pill that we gave you, so let’s find different alternatives.

Kevin Pho: So you mentioned, I don’t remember the number, about 15 percent of people have this reaction, this reward deficiency that gives them a euphoric response when they take an opioid for the first time. What are some other responses in that spectrum of genetic variations? Besides the euphoric one, what are some other examples of genetic responses to first-time opioids?

Amy Baxter: You mean things to watch out for?

Kevin Pho: Yeah.

Amy Baxter: Slurred speech was one that was much more likely in those who went on to get opioid use disorder. Being afraid that you’d never feel this happy again. Again, the sort of transcendent feeling, and wishing that everybody could feel this good. So it’s a lot of superlatives, but I think the slurred speech also really stuck out to me as an objective sign that someone else could look at and see.

And the thing is, I think we’re still in a nascent place with this. In my article I cite the people who have this list of 10 different genes, and while they’ve narrowed them down, there are also genes for depression and genes for ADHD. It’s really all of these attributes. So if you have ADHD, like me, you keep doing more extreme things, or more frequent things, to get the same reward sensation as somebody else. Then there’s the whole axis of depression, where it’s really a serotonin deficiency, and sure, we use reuptake inhibitors, but there are also different things, if you know that this genetics is there, like diet changes.

But I think all of those together go back to my initial reason for doing all this and writing all this, which was to overcome some of the residual damage that the Sacklers and Purdue Pharma left us with. We started looking at pain management as if the goal is pain-free, the answer is a pill, and opioids aren’t addictive. Now we know that they are addictive, but we still don’t really understand the degree to which there are risks, and as we’re quantifying those, we have left this big dearth in what we do as an alternative. A lot of that is very neurotransmitter-based. There are serotonin activities we can do that decrease pain. There are oxytocin activities, after a surgery or something, like friends and family and faith, that we can do to decrease pain.

So we need to limit opioids even further, but we’re still believing what the Sacklers, or Purdue Pharma, told us, which is that pain-free is still the goal and a pill is how we get there. I think that’s part of what we need to disabuse people of. Because so many people get opioid use disorder directly from their friends’ and family’s medicine cabinets, if we throw away those pills, if we quit prescribing those pills, then we’ll turn off the faucet of new opioid use disorder. But the subsequent corollary is that we have to understand pain better, so that we can do that ethically and provide other alternatives.

Kevin Pho: So you’re saying that some people are so genetically predisposed to opioid use disorder that even a perceived minimal dose of opioids, like a Tylenol No. 3, could set them on a path to opioid use disorder just because of their genetics?

Amy Baxter: Actually, yeah. It’s not a sufficient condition, but it can be part of the necessary condition. It is necessary: If you never take an opioid, then you’re not going to get addicted. Interestingly, there’s another study from 2008 that asked people on chronic opioids, some who do have opioid use disorder and some who don’t, what they remember from their first time taking one. The ones who don’t have opioid use disorder don’t remember anything special. The ones who do remember this euphoria. It’s something like eight- to 16-fold more common that they remember this euphoria. So if we can avoid it, even in the emergency departments, if we can avoid something that makes them feel that way, then that’s important.

Now, I think that opioids during surgery, when you’re out, aren’t a risk. In fact, there are many studies that show that morphine in the first 24 hours after a trauma or a burn reduces PTSD and chronic pain. So some of what’s going on here is complicated. There are places where the IV opioids are useful and are distinguished from just relief of pain. That was one of the places that the 14 percent came from, because one article looked at euphoria versus relief of pain in people with long bone fractures who had never had opioids before, and for 86 percent of them it was just relief of pain. But that 14 percent were also joyful, fantastic, just giddy with how much they loved the world. That’s different.

Kevin Pho: Now, how would we even screen for something like this? Do we simply ask qualitative questions, like, did you get euphoric in whatever scenario? Do we quantify it by measuring neurotransmitters? What’s your approach to screening for something like this?

Amy Baxter: Yeah, I am the messenger. This is not my area of research. It’s just what I’ve started to read about, in trying to understand how the downstream effects of pharma that seemed like a good idea at the time end up causing problems. I imagine ultimately, well, there are people who cannot process tramadol into an active mu receptor form, and there are people who cannot process codeine. These are different cytochrome P450 2D6 genotypes, and we can screen for those. The flip side of that is that there are people who metabolize them so quickly that it may cause them to get a rush. It may not just be a dopamine receptor thing. It may be that they’re metabolizing it so quickly they get this whoosh, and we can screen for that. It’s just a matter of prioritizing whether we do that or not.

But here’s one of the things, Kevin. As a little example, there are a lot of people now using the Buzzy device, including pharmaceutical companies that are using it in their CROs to do PK studies, to see whether there are site reactions or pain. But downstream, once a drug is approved, they’re not making the things that got those results available to the patients. So the FDA and pharma companies approve the safety within this narrow period of time, but they don’t look at what’s happening long-term. And I think the FDA in particular is starting to realize this and starting to look at some of these specific items: OK, if we’re going to do this, we do need to be testing, and it’s not just about efficacy downstream, it’s also about the unintended consequences that aren’t related to the labeling. So I think that’s incumbent. If you’re going to put a medication out there, you need to know what the long-term effects are.

I do think we’ll be screening in the EDs. After the TED Talk that I did on pain and opioid use, and it’s called “Pain brain hacks,” go find it, it’s good, one of the things TED did was say, “Hey, you talk about this euphoria. Where’s your data on this?” Because 6 percent of kids who had their wisdom teeth out got opioid use disorder within a year. So I showed them that paper, and they said, “Yeah, but tell me about the euphoria part,” and there actually was very little that was published. Because of that, I went back to my contacts at NIDA, the National Institute on Drug Abuse, and I said, “Hey, guys, this would be a great area. What are we doing?” And it turns out they’ve got an RFA, a request for applications, now that is asking about pre-addiction and studies looking at what happens before you get OUD. So I think there is now an area of research push for this. We’ve got some retrospective studies looking at the different characteristics, and we’ve got some genetic studies, and I think we’ll start putting those two things together to get a better way of identifying this going forward.

Kevin Pho: We’re talking to Amy Baxter. She’s a pediatric emergency physician, she’s the CEO of Pain Care Labs, and today’s KevinMD article is titled “Misunderstandings about opioid use disorder.” So Amy, from a broader standpoint, what is the general reaction to your findings that there is a genetic predisposition to opioid use disorder?

Amy Baxter: Well, they’re not my findings. I’m a curator; that’s not my area of research. But I think the general reaction is that people are so used to hoarding a few extra opioid pills in their cabinets, because we’ve built it up as being the good stuff. We’ve built it up as the way to treat pain. So when people find out that opioids actually just activate the reward center, that they’re making you not care about pain but they don’t impact pain, that’s a huge surprise to a lot of doctors, too.

So I think the reaction now is starting to be a realization that the way we process opioids, and the differential risks, emphasize again that we’re the only country that has this problem, and the problem we’re trying to solve with opioids is post-op pain. Most of our problem with opioid use disorder comes directly from prescriptions for post-op pain, either directly or from pills left in medicine cabinets. So I think what people are realizing even more is, I really do need to throw away these leftovers. The leftovers are making kids feel like these pills are benign and familiar, so when they’re laced with fentanyl, and now one in four overdose deaths is from a fentanyl-laced pill disguised as a Percocet or a Tylenol No. 3, that familiarity is part of what’s causing our opioid crisis and those deaths.

So with all of this together, there’s a rising awareness that pain is what we need to address. These pills are the problem, not the solution. And hopefully people are realizing that the predisposition to becoming hooked on a powerful reward is really out of people’s control, and the best way we can control it is to not let that exposure happen.

Kevin Pho: And my final question, Amy: Tell us some of the take-home messages that you want to leave with the KevinMD audience.

Amy Baxter: All right. Throw away the pills in your cabinet. Use other neurotransmitter-based pain relievers, which would be activities and different physical, fear-reducing and control-increasing options. And go watch the TED Talk with the pain hacks for additional ways to use options instead of opioids.

Kevin Pho: Amy, thank you once again for coming back on the show and sharing your time and insight.

Amy Baxter: Thank you for the forum, and for making a place where doctors can spout off and be collegial.