Gut Check: Douglas Drossman, MD, on Treating DGBIs With Neuromodulators

Dr Brian Lacy brings Dr Douglas Drossman back to Gut Check for a follow-up podcast on disorders of gut-brain interaction, to review the use of neuromodulators in treatment.
 

Brian Lacy, MD, is a professor of medicine at Mayo Clinic-Florida in Jacksonville, Florida. Douglas Drossman, MD, is Professor Emeritus of Medicine and Psychiatry at the University of North Carolina School of Medicine and founder, President Emeritus, and CEO of the Rome Foundation.

TRANSCRIPT:

Welcome to Gut Check, a podcast from the Gastroenterology Learning Network. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida. I am absolutely delighted to be speaking today with Dr. Douglas Grossman, professor emeritus of medicine and psychiatry at the University of North Carolina in Chapel Hill and founder, President Emeritus and Chief Executive of Officer of the Rome Foundation. Dr Drossman has been a driving force behind the Rome Foundation and the Rome criteria for the past 30 years. As many of our listeners know, Dr. Drossman is an expert in the field of functional bowel disorders, now called disorders of gut-brain interaction and abbreviated as DGBI, and we may refer to that today.

He has authored hundreds of books of peer-reviewed publications, most of which have focused on disorders of gut-brain interaction, and has lectured extensively throughout the world on these common disorders. Finally, he's a strong advocate of the value of good communication skills to improve the patient-provider relationship. He has set up highly successful training programs to teach providers how to optimize their care of patients.

In November of 2023, I hosted a gut check podcast with Dr. Grossman to discuss disorders of gut-brain interaction. We didn't focus a lot on treatment at that time because it was important to lay the groundwork, but today we'll focus on the treatment of these disorders with an emphasis on the use of neuromodulators. So Dr. Grossman, welcome. What a delight to have you back.

Let's begin really simply. What are neuromodulators?

Dr Drossman: Yeah, a good question. It's a new term that we're using. Unlike neurotransmitters, that typically have direct and rapid effects on receptors, post-synaptic receptors, neuromodulators can alter the strength and efficacy of synaptic transmission in a more prolonged manner. So we're talking about modulation of brain-gut circuits, which is what we're using with these medications in terms of treatment.

Dr Lacy: You know, in the past, we used a variety of these agents, and we're going to go through those agents shortly, to treat disorders, other medical disorders, and we call them antidepressants. Why the change in nomenclature now?

Dr Drossman: I think by evidence of how rapidly this term is taken on, it tells us that there was a real need for a new nomenclature. Back in the ‘50s and ‘60s, the treatments were targeted toward depression, anxiety, schizophrenia, and the drugs were called antidepressants, antianxiety and antipsychotics. And what we've done in the DGBI field is borrow those agents from psychiatry for treating psychiatric disorders to normalize dysregulated brain-gut function circuitry.

And so using neuromodulators is more scientifically valuable for what it's purpose is. And I think the most important thing about that, going with the dualistic system that we talked about last November, is that there is a stigma to it for patients with these medical problems. So in fact, using neurotransmitter… neuromodulators is far more accepted and easier to prescribe to patients rather than using antidepressant or antipsychotics.

Dr Lacy: Absolutely. Sometimes that label, that word choice is so critical and you've touched on already, but just to clarify for our listeners, really what is the overarching theory of why neuromodulators might help these patients with DGBIs, disorders of gut-brain interaction?

Dr Drossman: Yeah, the terminology goes hand-in-hand with the change in these disorders from functional GI to disorders of gut-brain interaction, because we're understanding this as dysregulation of the brain -gut axis. And by using neuromodulators, what we're doing is re-regulating that system.

This is usually seen in terms of pain, in terms of nausea or vomiting, or even altered bowel habit. So what we're doing is normalizing what's a dysregulated system. And it can do that through improving visceral hypersensitivity that is raising sensation threshold. It can affect motility. It can affect regulation of the brain pain control centers on the dorsal horn. And it can even lead to what we call neurogenesis when using it over time. It may rewire the system back to the prior state.

Dr Lacy: I like that last comment and many of our listeners may want to employ that, that for many of our patients, they really kind of have a wiring problem, don't they? And that these agents can improve that. I like that a lot.

Before we discuss some of these specific agents, you wrote a very nice review article just a few years ago, published in Gastroenterology, discussing the use of neuromodulators. And you broke those agents down into centrally acting agents and peripherally acting agents. Really, what's the difference there? And is it important?

Dr Drossman: Yeah, because we're talking about the central nervous system and the enteric nervous system. So central neuromodulators work primarily in the central nervous system— the antidepressants, the antianxiety, the antipsychotics. It doesn't mean they don't have peripheral effects. Similarly, the agents that are peripheral neuromodulators would be working on the enteric nervous system, like halosachan or linaclotide or gabapentin. That doesn't mean they may not have central effects as well, but the primary focus for a central is at the brain level and for the peripheral is at the gut level.

And another way to look at it, the peripheral neuromodulators are the gut-related treatments that we use for diarrhea, constipation, whereas the central one are often pain, nausea, vomiting, and the like.

Dr Lacy: Wonderful. And that's a nice segue into discussing some of the most common disorders of gut brain interaction, such as IBS—irritable bowel syndrome—and functional dyspepsia. And when we think about those two major categories of DGBIs, when do you decide to use a neuromodulator in your practice?

Dr Drossman: I think that's changing. If I was in this discussion 10 years ago, I would say, yes, we use, I would then say antidepressants and antianxiety agents. When patients have comorbidities like anxiety and depression, or when the symptoms were so severe, they don't respond to the usual treatments on the gut.

And now what I would say is we have to dig down into the mild to moderate group, too, because they can often be used as primary or even concurrent with the usual peripheral agents on the gut.

So I would say that now when the patients have symptoms of pain or nausea or vomiting or dysregulation of the gut in terms of motility that's not fully being treated by peripheral agents, I would go to this, but again, I could also use them as primary treatments in some patients.

Dr Lacy: Wonderful. And so before we start going through each of these agents, we discussed how words can be so critical and how we've transitioned with the language. So to help our listeners, when we think about how to explain these agents and why we use them to our patients, are there a couple of key phrases that maybe you could teach our listeners how to use to introduce this concept to our patients?

Dr Drossman: Yeah, I mean, I've said it already to some degree, that we are using these medications not specifically to treat psychiatric conditions like anxiety or depression, we're using it to normalize a dysregulated brain-gut circuitry. And that requires in the beginning to discuss what the brain-gut axis is.

If you give them that background, then you could say how you normalize it. And then you could try to address the stigma by trying to get to some of the feelings that they've heard from friends. And you could say, you know, you can use aspirin to treat pain, but you can also prevent a heart attack. And these agents have multiple purposes. Yes, they can treat psychiatric conditions, but they can also treat abdominal pain or nausea and vomiting.

And if you happen to have anxiety and depression, which is not unexpected when you have chronic GI symptoms, then it can help that too. So it can have a dual purpose. So you're giving them the rationale as to why you're using it.

Dr Lacy: Yeah, and I think that's that educational component that makes a patient-provider visit so effective. So if we hone down a little bit, let's think about tricyclic antidepressants. And as a group, these are some of the most common neuromodulators used to treat disorders of gut-brain interaction. At a global level how do these agents really work?

Dr Drossman: Well they can work centrally and they can work peripherally. The peripheral effect which people don't always think about in terms of pain is that it can actually reduce gut signaling, the visceral hypersensitivity, can actually reduce the signaling occurring at the gut level so that there's less throughput transmission from -- it's kind of raising sensation threshold.

At the central level, it's acting on the descending inhibition to the dorsal horn. So, when a signal goes to the brain, it goes to the dorsal horn. and then goes up to the brain. It's received in several areas of the brain, the saliency area, the singular cortex, which then interprets and sends down signals to the dorsal horn to block or gate the mechanism. It's called the gate control. This can enhance this gating mechanism so you can get increased down regulation to the level of the dorsal horn to block the signals going up. And then over time, it can also improve the neuro-deterioration that can occur. When patients have chronic pain or psychiatric disturbance or abuse, all of those conditions can lead to a decrease in neural axons at the level of the pain regulatory area like the cingulate, and this has shown some evidence that it can actually increase the neurogenesis or the growth over time, which is why, by the way, we keep them on the medications not just for a few weeks when they get better through the monoamine hypothesis of working at the synapse, but because they're working at the level of the brain to regrow neurons, we keep them on it for 6 months to a year before we taper them off so they don't relapse.

Dr Lacy: And that's such a great teaching point that at least I tell my patients, this is not something you try for a week or two. This will be many, many months and sometimes 6 to 12 months before you may realize the full potential benefit. So that's a great teaching point.

Doug, thinking about these tricyclics a little bit more, we know we have tertiary amines such as amitriptyline and secondary amines such as disipermine. How do you choose one medication versus the other? You know, really in essence, which medication for which patient?

Dr Drossman: If you're using a tricyclic, so let's say someone with IBS, you want to use a tricyclic for their abdominal pain, which is part of the criteria, you might also want to look at their bowel habit, because the tertiary means have more antimuscarinic and anticholinergic activity, they can cause constipation. And so if someone has IBS-D, you can use it to your advantage, something like amitriptyline or imipramine, whereas if they have IBS-C with constipation, you might go with the secondary mean like the desipramine or nortriptyline, which don't have as much of the anticholinergic and antimuscarinic effects. And so generally, we used the desipramine in a NIH study about 15 years ago and found that it didn't have really significant worsening of the constipation, whereas the amitriptyline would be causing constipation. So that's when I would choose the desipramine. So we can look at the bowel habit. In terms of the pain, they're probably equivalent.

Dr Lacy: Okay, wonderful. Let's shift gears just a little bit and discuss SNRI, serotonin- noradrenaline reuptake inhibitors. An example might be duloxetine. So how do these agents work at improving these disorders of gut-brain interaction?

Dr Drossman: Well, they work in the same way that I just mentioned. The difference is that I tend to prefer the SNRIs because they have virtually none of the anticholinergic, none of the side effects that you see with the tricyclics.

The main side effect, which occurs in about 15% of patients, is nausea. And you can treat this by attrition over time as they get better or you can give it with a meal; we start with a low dose, we might go up, but you don't get these other side effects which can be very limiting. You know in our NIH study we went up to 150 milligrams of desipramine you know what we often see is people using 10 or 25 milligrams of amitriptyline, which is okay. In fact, Alex Ford just came out with a paper last November showing that 10- to 30-milligram doses can improve global symptoms of IBS. But, you know, Brian, the patients you and I see, they did that in primary care, are often more severe, and you have to go to higher doses.And when you have to go to higher doses, you get the side effects with the tricyclics. But we can use SNRIs at full doses without those side effects.

Now, the data is really around the tricyclics. This is where most of the studies are, and that's where the guidelines come from AGA and ACG. But most of what we do is off-label. SNRIs have proven value in chronic pain with other conditions like fibromyalgia, diabetic pain, chronic back pain, migraine. It just hasn't been studied as well in the DGBIs, but that doesn't mean we can't use them off-label. And it's really my preference.

Dr Lacy: So a couple of great teaching points. One is, be ready to use these agents. They're effective. We have lots of good data. Number 2, you mentioned Alex Ford's ATLANTIS trial with a lower-dose tricyclic agent, but that's from primary care and not really the referral patients that you're seeing. And number 3, you know, give us time to work and don't be afraid to push the dose and get comfortable with that.

So thinking a little bit about more about SNRIs and which patient do you think is more likely to respond to an SNRI such as duloxetine. Do you have a patient profile that maybe is a better likelihood of responding? And how long do you give them a fair trial before you say, you know what, this is just not the right drug for that patient?

Dr Drossman: Well, again, I tend to start with SNRIs, but where others might start with a tricyclic and they're limited by the dosing because of side effects where they're not seeing benefit, then they should switch to an SNRI. That would make perfect sense, and you can get up to 30, 60, even 90 milligrams without much problems with the side effects. It doesn't cause the same degree of constipation that the tricyclics do, even less so than the desipramine, because they don't have as much of the, you know, cholinergic effect that I mentioned before.

I usually try to reach a target dose of 60 milligrams. So what I'll do is I'll put them on 30 milligrams and monitor them for a week or two. And if they're having no side effects, then I'll go to 60 because, I'm looking for 60 as the target. Other people feel more comfortable starting it on 30. I really think that to get real benefit you need to be on 60, though many could occur on 30. I just don't see the advantage if they're not having side effects because I want to maximize the effect. If they're going 4 to 6 weeks and I'm not seeing benefit, I generally will go with 1 of 2 options. I might increase the dose to 90 since they haven't had some effects and I might see a partial effect or I might add a second agent, an augmentation agent, which could be brain-gut behavioral therapy as a second augmenting agent, or it could be another agent like an atypical, like Seroquel is one that I often use a lot, Sinequan—quetiapine, I'm sorry, not Sinequan, quetiapine, or sometimes olanzapine. So those are your options, what you can do over time without needing to get a psychiatrist in.

At that point, if it's still not working, you might want to bring a psychiatric consult, but keep in mind what we're teaching, many psychiatrists don't know about. We're teaching these agents for GI problems. They may not be as familiar that olanzapine is used for nausea and vomiting. So that's where you got to get with a colleague who knows what they're talking about.

Dr Lacy: Wonderful. So I want to summarize that for our listeners for these great takeaway messages. One is be comfortable using an SNRI, which has good data supporting pain relief. Feel comfortable pushing the dose, give people time to respond, and then if there's only a partial response, don't be afraid to add on a second agent. We do that for a lot of other disorders and that second agent may be a tricyclic, it may be behavioral therapy, it could be any other thing. So feel comfortable using that to really get maximum efficacy.

Dr Drossman: We, many years ago with Dr. Amato Grover, when he was here, took our group of patients, it was about, I remember 39 patients, no, it was about 22 patients, who were on either a tricyclic or an SNRI for a month without benefit. And we added Seroquel in low dose. We're talking 25, 50 milligrams, maybe 100 at the most, not the 800 used in psychiatry. And we found 50% meaningful improvement in that group. So it is, it can be augmented. There's just aren't enough studies yet that are proving it's a certainty.

Dr Lacy: Yeah, wonderful. That's impressive results. And you mentioned briefly, a tetracyclic antidepressant. Let's think about mirtazapine, which is a tetracyclic antidepressant. I found this very useful in my practice for a variety of reasons. How does this work? And do you think there's a group more likely to respond to it than others?

Dr Drossman: Well, mirtazapine is a complex agent, much like a tricyclic, which has adrenergic activity, muscarinic, cholinergic, antihistaminic, serotonin, and norepinephrine. So we call it a dirty drug because it can have multiple effects. And we can use that to our advantage. It does have some pain benefit, but not as much as a tricyclic. It does have some benefit, though, primarily for us, in terms of nausea. It can be a little bit constipating and it could be sedating.

So the kind of patient that I might use this for, either primary treatment, would be someone who had chronic nausea-vomiting syndrome, or Jan Tack has shown it could be used for patients who might have post-prandial distress syndrome or functional dyspepsia, working at a central level. But for pain of IBS, I wouldn't use it as a primary agent.

But if they do have inadequate benefit with a DGBI and they have dominant nausea, I would add a low dose in their mirtazipine to whatever neuromodulator they're using, maybe 7 1 /2 milligrams or 15, but not the high doses. So PDS, nausea-vomiting syndrome, if sedation is needed, because of its side effects, particularly the histaminic effect, you can gain weight with this drug more than others, including more than the tricyclics. So you have to watch that, particularly in young women who are very concerned about that.

Dr Lacy: Great teaching points. And as you mentioned, if somebody also has poor sleep, disordered sleep, that can be beneficial as well. So a lot of bang for the buck there.

Shifting gears again as a pirone such as buspirone can be very useful in our treatment of patients with DGBIs. How do these agents work and which DGBI do you think an agent like buspirone is best suited for?

Dr Drossman: Yeah, I don't think we know for sure how it works. In psychiatry it's an antianxiety agent acting through a GABA mechanism rather than a benzo mechanism. So in psychiatry, for general anxiety disorder, they would use buspirone rather than a benzodiazepine.

It's also used in psychiatry as an augmenting agent, just like the atypical antipsychotics. So in some cases, we add buspirone to a tricyclic to enhance the benefit, just like we would add Seroquel. So it tends to be safer. You can get a bit of headache from it, but no major side effects. Some patients do find it hard to tolerate, but in the low doses, it's okay. And then Jan Tocke had published a paper several years ago showing its benefit in PDS, post -prandial distress syndrome, which is as you know, the failure of receptive relaxation of the stomach, which leads to the early satiety and some bloating sensation and inability to complete a meal. And it seems to increase the relaxation, reduces the tension in the gastric muscle wall, which allows it to accommodate more food. So we I often use it as primary treatment in patients who have post-prandial distress.

Dr Lacy: Wonderful. Doug, as we start to wind down here, I want to clarify, maybe we could even call it a myth or misconception about SSRIs—selective serotonin reuptake inhibitors. And a lot of providers use SSRIs to treat visceral pain. But is that good practice? Are they effective?

Dr Drossman: No, it's not. And multiple studies have shown this. There are a few studies that have shown global improvement of symptoms in esophageal chest pain, but that doesn't mean the SNRIs won't be better. They just haven't gone head-to-head, but the studies that have looked at the bowel symptoms, it doesn't really help at all.

The problem is what we've learned. We did a study with Ben Nelson and Lin Chang of 650 gastroenterologists about their comfort level with medications and tricyclics and SSRIs are up there, but SNRIs and atypicals are really down in terms of their comfort level and their familiarity with using it. And because they're not, the Rome Foundation is really working hard to educate the gastroenterologists on the differences between these ages. That's why I'm so glad to be doing this with you, to provide that level of education.

No, you don't use SSRIs for IBS symptoms in general. You can use SSRIs for anxiety, if the pain is not a dominant feature. It might be mild, and you're using peripheral neuromodulators to treat it, like linaclotide, but if they have a level of anxiety, then you can add it.

It is possible to add it to a tricyclic because you're usually using low doses of the tricyclic, 25 or 50 milligrams, to a typical 20 milligram of an SSRI, you usually don't have to worry about serotonin syndrome because there's not that much serotonin in those doses of tricyclics. Far more worry if you go from 40 to 60 of an SSRI than using 20 with the 50 milligrams of a tricycle.

Dr Lacy: Wonderful. Doug, this really has been a wonderful conversation, so thank you. And before we sign off, any last thoughts for our listeners?

Dr Drossman: Yes, we have a paper coming out that just got accepted in the red journal. It's called "Central Neuromodulators and Irritable Bowel Syndrome: Why, How, and When.” Ignacio Hanna and myself are coauthors on this. It just got released yesterday, so you can get it online. And what we did with this journal is we took the Rome working team and brought it forward. That was 5 years ago. And we're talking now about what dose, all the things we talked about—what dose to use, it talks about how you take them off it, how you avoid problems in reducing the dosage, and a lot in the side effects. So it's really a complete article that I highly recommend.

Dr Lacy: Wonderful. So for our listeners today, you've heard this great explanation about these medications. But if you learn best, maybe by reading, we've got something coming out in the American Journal of Gastroenterology, authored by Dr. Grossman and Hanna, that will be a great, great follow up to this podcast today. So Doug, again, thank you so very much. We know how incredibly busy you are. We really appreciate your time today.

To our listeners on Apple, Spotify, and other streaming networks I'm Brian Lacy, a professor of medicine at the Mayo Clinic in Jacksonville, Florida. You've been listening to Gut Check, a podcast from the Gastroenterology Learning Network. Our guest today was Dr. Douglas Drossman, emeritus professor of medicine and psychiatry at the University of North Carolina, and founder, emeritus president—excuse me, you've got so many emerituses there— and current CEO of the Rome Foundation.

I hope you found this podcast as enjoyable as I did. I know it is quite educational and I look forward to having every listener on future podcasts as well. Stay well. Thank you.