Medical Therapies for IBS-C: Expert Roundtable Part 3

Our expert panel continues as Drs Cash, Lembo, and Riehl delve into the existing medications available to treat IBS-C, from neuromodulators to secretagogues and the sodium/hydrogen exchanger (NHE3) inhibitor tenapanor. 

Anthony Lembo, MD, is a professor of medicine at the Lerner School of Medicine at Case Western Reserve at Cleveland Clinic in Cleveland, Ohio. Brooks Cash, MD, is a professor of medicine at Texas A &M School of Medicine and the medical director of the Functional Bowel Center at Baylor Scott & White at Baylor University Medical Center in Dallas, Texas. Megan Riehl, PsyD, is a GI psychologist and an associate professor of medicine and the clinical director of the GI Behavioral Health Program at the University of Michigan in Ann Arbor, Michigan.

CLINICAL PRACTICE HIGHLIGHTS

IBS-C Treatment Landscape: OTC Laxatives, FDA-Approved Secretagogues/Retainagogues, and Adjunctive Pain Strategies

• First-line and OTC approaches in IBS-C: In irritable bowel syndrome with constipation (IBS-C), osmotic laxatives (polyethylene glycol, magnesium-based products) improve bowel function but not pain; lactulose is often avoided due to bloating. Soluble fiber and osmotics may be combined for synergistic effects, though bloating can worsen and may require fiber adjustment. Stimulant laxatives can be used as adjuncts but may exacerbate abdominal pain and are discontinued if poorly tolerated.

• FDA-approved and prescription therapies: Evidence is strongest for FDA-approved agents, despite cost and insurance barriers. These include secretagogues—lubiprostone (chloride channel activator), linaclotide and plecanatide (guanylate cyclase-C agonists)—and the retainagogue tenapanor (sodium/hydrogen exchanger inhibitor). These largely nonabsorbed drugs act via fluid mechanics, commonly cause diarrhea, and have minimal systemic effects. Lubiprostone is FDA-approved for IBS-C only in women at 8 mcg twice daily due to phase 3 trial enrollment limitations. Prucalopride, a 5-HT4 agonist prokinetic, is approved for chronic idiopathic constipation but used off-label for IBS-C.

• Treatment selection, bloating, and pain management: No head-to-head trials exist; selection is individualized based on symptom profile, tolerability, and insurance coverage. Linaclotide is often perceived as more potent; tenapanor may be favored when abdominal pain predominates. Diarrhea with one GCC agonist often predicts class intolerance. Bloating may improve with constipation relief; adjuncts include enzyme preparations (lactase, fructan hydrolase, alpha-galactosidase) for meal-related symptoms, pelvic floor biofeedback for suspected dysfunction, and breathing exercises for abdominal phrenic dyssynergia. Persistent pain despite bowel improvement is commonly treated with low-dose tricyclic antidepressants (e.g., desipramine, nortriptyline), titrated every 3–4 weeks.

TRANSCRIPT

Dr Lembo: So let's move on and talk a little bit about treatments. Brooks, you sort of alluded to the osmotics. Of course patients are constipated and we know that PEG and magnesium-based products, we don't tend to use lactulose unless you tell me you do in your practice because of the bloating that can occur, and those are the most common of them. They don't help pain as you mentioned, but they do help bowel function, right? So I think that data is pretty clear. Do you ever use the stimulants or do you go osmotic and then move on? I think that's what you were starting to say.

Dr Cash:

I do use stimulant laxatives recognizing that in some patients that may worsen their pain. And you mentioned bloating, and I think it's worth mentioning that bloating is not part of the criteria for irritable bowel syndrome. There is actually a DGBI called functional bloating and distension, and that's without the bowel habit symptoms. But certainly we see, I'd say probably 75, at least in my experience, 75 to maybe as high as 90% of patients with IBS in general will have some degree of bloating. And actually in some of the guidelines from some of our professional societies, the first line on the table is if the patient's constipated, this is for bloating and distension treat the constipation. So very common symptoms. Now our fiber sometimes can make that worse, but I often will use the osmotic and the bulking agents or soluble fiber together. I do think that you can get a synergistic effect in those patients recognizing that if they have bloating, bloating may get worse.

You may have to drop the fiber or find an alternative source of fiber. You don't want to necessarily use insoluble fiber. There's pretty good data that shows that that can bother people. Same thing with stimulant. Laxatives can be beneficial and I do often use those as adjunctive therapies recognizing that they may make patients abdominal pain worse. And if that happens then we cease and desist and we move on to other things. But I think there is a role for those over the counter therapies, at least initially. And then we may have to escalate to other drugs.

Dr Lembo:

Let's move on and talk about those other drugs. What do you have up in your armamentarium?

Dr Cash:

Well, for FDA-approved therapies, which have the best evidence, so it's kind of ironic that we try to use nonFDA-approved therapies and our patients love to do alternative therapies, but the best evidence really surrounds the drugs that are FDA-approved. They're also the most expensive and they're also often the most difficult to get approved from insurance companies. But there's, I tell patients and describe them as basically being in two categories. We have what I call the water hoses or the power washers, which are the drugs that bring fluid into the gut or they retain fluid. We have 3 that work to cause more fluid secretion. We call those secretagogues and that includes lubiprostone, which is a chloride channel activator, and then 2 GCC agonists or guanylate cyclase agonists and ide. And then we also have what's called or being called a retainagogue, which is a medication that retains sodium in the gut and then retains chloride and thus retains fluid, and that’s tenapanor.

And so for drugs that all work basically through fluid mechanics and the theories are that that extra fluid may solubilize or add more water to the stool may actually cause some distension, perhaps there's some increase in motility. There's some data, especially with some of the secretagogues and tenapanor, that there might actually be an effect on the enteric neurons to help with the pain of irritable bowel syndrome. So probably a multitude of actions.

There's also another drug out on the sidelines, not FDA-approved for irritable bowel syndrome constipation, but I use it quite a bit. This is one of the reasons I in my practice, give patients both diagnoses. This drug's approved for chronic idiopathic constipation, prucalopride, which is a prokinetic therapy. It works on serotonin, it is absorbed into the blood. It's a type 4- serotonin receptor agonist and it increases motility. So it's a prokinetic therapy. It's the only one of those 5 that does that. And it's not approved unfortunately for IBS with constipation, but I often will use that in my practice for these symptoms.

But generally I'll start with one of those therapies and then we move on. The nice thing about the secretagogues and the retainagogues is that they're largely nonabsorbed, so their major side effects are diarrhea. They don't interact as far as we know with other medications. They don't cause systemic side effects other than diarrhea. And so in that respect, they do add a level of safety,I think. If patients do have an adverse event, we simply stop them and that adverse event typically will fix itself and remit very, very quickly.

Dr Lembo:

I think it's worth noting that diarrhea obviously is the most common side effect I think for all of them. And again, usually it goes away after you stop it. Patients often adjust to it pretty quickly. Lubiprostone, which is worth noting is approved only for women for IBS-C at the dose of 8 micrograms twice daily, there's a higher dose for chronic idiopathic constipation, 24, which is approved for both men and women. I tend to use them interchangeably in practice, but just as worth noting that.

Dr Cash:

Tony, I want to just add to that. That's often a thing that vexes practitioners, why is this drug only approved for women? And it's a real simple answer in most cases—it's because the studies, the phase 3 studies that these companies did and put before the FDA were underpowered in men. As far as we know, a chloride channel in a man is just the same as a chloride channel in a woman. But the IBS studies for lubiprostone did not have enough men in them to show statistical difference or benefit in men, so the FDA only approved it for women. So it's usually a very simple explanation, which unfortunately ends up actually affecting some of our patients sometimes.

Dr Lembo:

So we have 4 drugs. And do you have any tricks up your sleeve about which one you think is better or what do you do in your practice? What's the best? Is there a specific patient that you would choose one over the other?

Dr Cash:

There are. There is no head-to-head data with these therapies, I tend to use them after I've tried over the counter lifestyle, diet modifications, et cetera, and I've maybe gotten some benefit but not satisfactory benefits. So keep that in mind. I tend to think of linaclotide as kind of the heaviest of the hitters. I don't have any data to support that other than my experience, but I generally will start with a lower to middle range dose with linaclotide. If I really want to be gentle, I'd say I have an elderly female patient and I agree with you a hundred percent when you have new onset symptoms at a more advanced age, we need to be thinking about other organic diseases, but let's assume this person has got IBS-C symptoms, I may start at a very low dose of lubiprostone and then titrate my way up using a variety of the different doses.

In patients who have primarily an abdominal pain picture, I may opt to use tenapanor in those patients first because I do in my practice, see I think a very robust response. With regards to abdominal pain symptoms, I tend not to use the GCC agonists in place of each other. Let's say somebody gets diarrhea with linaclotide, I tend to not go to the other GCC agonists because I tend to see diarrhea in those patients as well. I think they're sensitive to that mechanism of action. So some of them I'll use in response to potential side effects. I don't have necessarily a favorite per se, but there are a few tricks to trade. The most pragmatic answer I can give you is whatever the patient's insurance will cover. And unfortunately that's often too often a reality in our practice.

Dr Lembo:

Yeah, I think as close as we get is a network meta-analysis and there's a lot of overlap on the overall efficacy. But as you indicated, there are subtle differences even within the GCC agonists, the linaclotide, there are differences, linaclotide is pH sensitive, so it's degraded quicker. And as you indicated, the tenapanor works by a different mechanism, which sometimes is going to be useful as well. And then of course, very severe patients may combine particularly severe constipation, would combine therapies maybe in some patients.

What about the bloating? know there's some data with some of the drugs for improvement in bloating as you indicated. Sometimes that improves it. Is that what your experience is with this?

Dr Cash:

Sometimes moving the bowels does improve the bloating, and as you mentioned, I do sometimes use combination therapy with the prokinetic therapy, with an osmotic as well. Now again, we're mixing and matching some of the diagnoses there. One of the things that I've started using more for patients with, especially meal-related bloating is an enzyme preparation that patients can get over the counter that has 3 different enzymes in it has lactase, fructan hydrolase, and something called alpha galactosidase, which those latter 2 are common FODMAP constituents. We were talking earlier about the FODMAP diet. This is a powder preparation that patients mix into their food and helps them digest some of those oligosaccharides that perhaps the microbiome is very happy to digest. And I have had some benefit in some patients with their bloating and distension, especially when it's meal related. So it's really important to get that history, whether it's not it's meal related.

The other thing that we've alluded to it, if we're not having significant response or satisfactory response, think about that pelvic floor dysfunction on top of these things. And sometimes you may need to test those patients and send them for biofeedback therapy and that will allow sometimes those laxative therapies to work in a more optimal way and may help relieve some of these additional symptoms.

Dr Lembo:

And the patient has persistent pain, their bowel habits are better. Are you jumping right to a tricyclic antidepressant or what would you do next?

Dr Cash:

I tend to go with the tricyclics and I tend to use the secondary amines because they have less side effects. That's medications like norpramin and desipramine. Most of the data actually supports amitriptyline, which is a tertiary amine, but it has more side effects. Again, I think it's largely tomatoes-tomahtoes, as long as you're comfortable with using those medications, very low doses, titrate them slowly, every 3 to 4 weeks. I start at10 or 25 milligrams at night. Sometimes I'll even use SNRIs if I really get a feeling for anxiety or depression in these patients. We'll talk about that. We use standard doses for those. I tend to start with the TCAs.

The other thing I'm going to jump back really quickly and mention for bloating that you mentioned. There's an evolving theory about, and it probably precludes our discussion today, but something called APD, abdominal phrenic dyssynergia. So it's a disconnect between the diaphragm and the abdominal muscles and there's evolving data showing that some breathing exercises similar to diaphragmatic breathing can be helpful for those patients. And I do send patients for that as well. And I'm actually in the process of learning how to administer that therapy for my patients. So I think that's something else for us to think about evolving in the future. But yes, I do use the tricyclics pretty quickly for those pain patients.