Approaching IBS-D Management: 5-HT3 Directed Therapy

An overview of 5-HT3 directed therapy’s role in treating irritable bowel syndrome with diarrhea (IBS-D).

Mark Pimentel, MD: We’ve talked about brain-gut, but that’s not what they’re saying anymore. They’re saying gut-brain axis. I’m not exactly sure of the evolution of that, but I surmise that maybe there is something going on in the gut that’s affecting the brain, and now there’s this brain-gut microbiome access. I’m kind of segueing into the microbiome. The microbiome can do all sorts of things, Dr. Rezaie. I know we talked a little bit about this, but can you provide me with a little refresher on the microbiome here and what you think is going on?

Ali Rezaie, MD: Well, the gut microbiome, as we talked about, is a very hot topic. There are trillions of bacteria in our body, and estimates are that there are more bacterial cells in our body than we have human cells. In a sense, you are more bacteria than human. And not unexpectedly, they are interacting with our bodies nonstop. This is 1 thing that I tell my students and my fellows. Bacteria have been around for hundreds of millions of years, and we have been around for just a few million years. So bacteria have figured out what they can do. They can produce whatever they want to produce, and from their eyes, you’re just a host. They want to keep us alive so they can survive. But at the end of the day, they look out for themselves. So they produce whatever they want.

Brennan Spiegel, MD: It sounds terrifying, by the way.

Mark Pimentel, MD: Those fellows are scared all the time.

Ali Rezaie, MD: But if you think about it, they can produce anything that they want, as we have seen at conference as well. They can produce serotonin, they can produce histamine, and they can produce sex hormones, estrogen, progesterone, testosterone. And they can affect us in multiple ways. We’re now understanding the role of the gut microbiome on even psychological health with the posters on brain fog, or depression, or even Parkinson disease and Alzheimer disease. And all the way through the way bacteria change the motility of the gut and to the way they change the function of other organs. We saw multiple studies on fatty liver disease and microbiome, which has opened this door to this new concept of gut-brain axis, meaning that the microbiome in the gut is interacting directly via the nerves with the brain as well, which is a fascinating new concept. And hopefully by modulating those pathways, we can help patients.

Mark Pimentel, MD: Let’s undo that terrifying story. For the most part, the microbiome is amazingly resilient and amazingly beneficial. The goal is not to get rid of all of them, because they help us. But yes, there are perturbations that we’re learning that are dysfunctional to the host. I think as we get more science, this is going to be pretty incredible stuff.

Let’s go on now to specific therapies. We kind of touched on antidiarrheals a little, so I’m going to skip right to IBS-D [irritable bowel syndrome with diarrhea]. Bill, you did some work on alosetron back in the day when it first launched and then relaunched. It’s sort of on the market, but people don’t use it all that often. Can you give us sort of a rundown of alosetron?

William D. Chey, MD: Yeah. Alosetron is a 5-HT₃ receptor antagonist, so it’s a drug that blocks certain types of serotonin receptors and is very effective at relieving abdominal pain and improving diarrhea. The baggage with alosetron has been around idiosyncratic cases of ischemic colitis. Patients develop abdominal pain and rectal bleeding attributed to ischemic colitis. The good news is that it is fully reversible when you stop the drug. The bad news is that it’s idiosyncratic, meaning that it’s not dose related, and we can’t predict who is going to get this complication. The other bit of good news is [that] it’s really rare. Probably 1 in 1000 patients get this complication. It’s a very rare complication. The other thing about alosetron is that it can cause dose-dependent constipation, which is not much of a surprise given the fact that it’s a diarrhea drug. The other alternative that you could think about in that category, though, is ondansetron, which is 1 that we’re all very familiar with for nausea and vomiting. There are now a couple of studies showing that ondansetron, like alosetron, is effective for IBS-D and doesn’t appear to cause the problems with ischemic colitis.

Mark Pimentel, MD: How often do you use alosetron or ondansetron in your practice? Which of the 2 do you like?

Anthony J. Lembo, MD: We generally start with ondansetron, and the typical dosing is 4 mg, 2 to 3 times a day, but you can go up to 8 mg, up to 3 times a day. That’s what the initial study did with it. So we’ll start there because of fewer adverse effects. Alosetron is part of a REMS [risk evaluation and mitigation strategy] program, so it does require much more discussion. Patients have to review a consent form that’s pretty straightforward, but it does raise a lot of eyebrows. And so, some patients will prefer to try other things first. Although in my hands, I think Bill would agree that it’s quite effective. For patients with severe disease who have failed other therapies—and again, it’s approved only for women, so we tend to restrict it to women—I recommend it. It’s quite effective.

William D. Chey, MD: Women with severe IBS-D. And I totally agree with Tony. It’s definitely a go-to drug for those patients for whom you’ve tried everything else and nothing has worked. It can be a very effective drug.