Brian Lacy, MD, and Baharak Moshiree, MD, on IBS: Part 2

In part 2 of their podcast on irritable bowel syndrome, Dr Brian Lacy and Dr Baharak Moshiree discuss the the various treatment options available and recommended under the new ACG guidelines.

Brian Lacy, MD, is a professor of medicine at the Mayo Clinic in Jacksonville, Florida. Baharak Moshiree, MD, is professor of medicine and director of the motility laboratory in the division of gastroenterology and hepatology at Atrium Health in Charlotte, North Carolina.

TRANSCRIPT:

Dr. Brian Lacy:  Welcome back to this Gastroenterology Learning Network podcast. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida.

I'm delighted to be once again speaking with Dr. Baha Moshiree, who is a professor of medicine and director of the motility laboratory in the division of gastroenterology and hepatology at Atrium Health in Charlotte, North Carolina. Our discussion today will be on the treatment of IBS.

It's really hard to have any discussion these days about IBS without mentioning the low-FODMAP diet, Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols. Why might this diet improve IBS symptoms and what's the data to support its use?

Dr. Baharak Moshiree:  There's plenty of studies, starting from Monash University, that came up with this low-FODMAP diet plan, and then others that subsequently done in the UK and then also, of course, in the United States comparing the low-FODMAP diet to the traditional even NICE diet.

FODMAPS are fermentable oligosaccharides, disaccharides, monosaccharides, and polyols. What these foods do, they increase water secretion and colonic fermentation. They interact with the gut bacteria. As a result of this fermentation, there are gasses that are produced that can cause distention of the intestinal wall, and then the symptoms of irritable bowel syndrome, the abdominal pain and bloating. They also have effects such as diarrhea. We don't really understand the effects on the gut microbiome completely, but there is an increased intestinal permeability that's also seen in these patients.

Based on the several randomized control trials now that have been done, the abdominal pain in IBS and then the global symptoms, which is the important FDA endpoint, did improve after two to six weeks of this low-FODMAP diet.

It's a lot of legumes. Things like onions, there's grains, there's lots of fruits, artificial sweeteners, that are especially gas-producing and are fermentable in the colon that can cause these symptoms. So really it's an elimination-type of diet you want. One could say that's also a way to diagnose irritable bowel syndrome because we can identify certain foods that are problematic in our patient population that patient can then avoid. Then it'll be a much easier mechanism than going on pharmaceutical drugs.

There was low quality of evidence because sustainability of the low-FODMAP diet is hard. The studies, some of them were very heterogenous. For the most part, this is a standard diet that we recommend to our patients with irritable bowel syndrome.

Dr. Lacy:  Wonderful. One of the interesting things about the guideline, I thought, was that it not just highlights important things to do, but also highlights practices that we should not be doing. This guideline comes out against the routine use of smooth muscle antispasmodics. Why is that?

Dr. Moshiree:  We looked at the ones that were available, of course, in the United States. The 3 that we have available are dicyclomine, hyoscyamine, and hyoscine, which is scopolamine that's used for motion sickness. I use that frequently, actually, in my dyspepsia population and patients with nausea. But in irritable bowel syndrome at least, review of all these trials showed that these were very old studies—old, like in the '80s, some of them. I guess not that old. They were not as robustly done. Of course, the FDA endpoints were not often used. There was limited data. There was a significant amount of bias with many of these studies, so the quality was not as rigorous as the quality of the studies that are now done.

Because of the side effects of these drugs, which are constipation, dry mouth, and then their sedating effects, these are less desirable options. Most of the studies did not show any change in the bowel habits except for the fact that they can be constipating, so they may not be as well supported for the patients with IBS-C specifically. In diarrhea, there was no increased improvement in patients' symptoms versus the placebo.

Dr. Lacy:  Wonderful. Similarly, although probiotics are widely used by patients for a number of different conditions, the guidelines argue against the routine use of probiotics for IBS symptoms. What was the rationale there?

Dr. Moshiree:  This is where the guidelines probably get some pushback from patients. I have patients that come in every day—today, two of them—that take certain kinds of probiotics that they take out of a fridge and it has certain species of bacteria in them that are in the billions. They think that they have perhaps helped their symptoms.

Unfortunately, based on the 37 trials that we reviewed as part of the guidelines, many of the studies that are done are done on single species or just a few. We don't really know what species each patient needs because we don't know everyone's gut microbiome. Even review of the studies shows that probiotics did not significantly improve the global symptoms of irritable bowel syndrome. So at least for IBS, we were not able to make that as a recommendation. We recommended against it based on the decrease in gut diversity, like microbiome diversity that is seen with probiotics.

Studies that have looked at Lactobacillus and Bifidobacterium also did not show improvement in the global symptoms. The one that was the largest studied was Saccharomyces cerevisiae. That showed improvement 32% vs 26% on placebo. So at this point in time, we don't have enough information to make that guideline recommendation.

Dr. Lacy:  Nicely put. Again, this shows sometimes although there are multiple studies, because of the different doses, the different strengths, the different probiotics, and the different patients, our gut microbiomes are all different. I think we still have a lot to learn about this topic.

Polyethylene glycol, widely used to treat constipation. It's safe, it's not expensive, it generally helps constipation, but once again, the guidelines said don't routinely use this in IBS-C patients. Why is that?

Dr. Moshiree:  Again, the word there is routine. I am sure that there are gastroenterologists out there that use PEG for IBS-C. I think that's perfectly OK, even if it does disagree with the guidelines, because PEG is cheap right now. A lot of insurances are not covering even the pharmaceutical drugs that are available for IBS.

After review of the data, though, there were 4 trials using PEG for CIC. The four trials that were reviewed, there was no improvement in abdominal pain. In some of the trials, bloating actually worsened, although bloating is not part of the Rome IV criteria, for diagnosis of IBS, bloating is an important symptom that patients have. Since this was a side effect of PEG, it was not recommended. The global symptoms of IBS do not improve with PEG, which is why the guidelines did not recommend it.

Is it a cheap option for constipation? Absolutely. CIC and IBS-C, are they on a spectrum? Probably, but if abdominal pain is the main symptom we're also trying to improve, PEG did not improve that symptom.

Dr. Lacy:  That's a great way to phrase that, Baha. For our listeners who may not have read this, this is in the January 2021 edition of The American Journal of Gastroenterology.

A focus was on improving global IBS symptoms; pain, constipation or diarrhea, and bloating. Polyethylene glycol helps constipation but it may not improve those other symptoms, which is why it didn't get a great recommendation.

Let's shift gears again now to GCC agonists. These are the Guanylate cyclase-C agonists that are on the market, linaclotide and plecanatide. What's the data supporting their use?

Dr. Moshiree:  The data, Brian, on these is actually very robust because they had to meet the FDA endpoints: Sustained response, we know, and then also efficacy. They had to prove that there was an improvement in the patient's worst abdominal pain scores by 30%. Also, a complete spontaneous bowel movement that was achieved.

Constipation is defined as less than 3 bowel movements a week, so these had to be weekly for a big segment of the studies. For linaclotide, the endpoint was achieved up to 6 months, so that's a very long-term study on that specific drug.

Both of these drugs improved the visceral pain. They improved abdominal pain, bloating, and also the constipation symptoms. These did target the global symptoms in IBS. Of course because these are newer drugs, the FDA endpoints that are now important were all met.

Dr. Lacy:  Wonderful. For many of our listeners who are a little bit older, which includes me, they'll remember the story about tegaserod, which is a 5-HT4 agonist. It had this interesting history where it was brought to the market, was shown to be very helpful for many patients, then voluntarily withdrawn, and then reapproved by the FDA in 2019.

There's a lot of data supporting its use. In which patient would you consider using tegaserod?

Dr. Moshiree:  The recommendations are for women, because this study showed that...t here are plenty of studies on tegaserod, but this study showed improvement specifically in women. Now it's only recommended in woman less than 65 years of age who don't have any cardiovascular risk factors. Pretty much you have to have less than 1 cardiovascular risk factor or none, I would say, in my own practice.

The reason for this is because of the cardiovascular disease. There was an increase in men risk in patients who used tegaserod. Those affected 14 patients in the studies. That's why it was removed in 2002 when I was a GI fellow and thought this was the best thing in the world [laughs] because we had no other prescription drugs available for IBS-C, and then removed in 2007. Now it's re-entered the market in 2019.

It's for women with IBSC, less than 65 years of age, and no cardiovascular risk factors. The data on men did not really show any significant improvement. They didn't have enough men in the studies perhaps. Therefore, this is not a recommendation we make for men with IBS-C.

Dr. Lacy:  Baha, thank you. Let's talk a little bit about IBS with diarrhea. We've got some neat data over the last decade showing that anywhere from about 10% to 30% of patients with IBS and diarrhea may have some component of bile acid malabsorption as a cause of their symptoms.

However, the guidelines recommended against the routine use of bile acid sequestrants for the treatment of IBS with diarrhea. What was the rationale here?

Dr. Moshiree:  The rationale here is mostly because there's 2tests that can be done for bile acid diarrhea. It's prevalent in 1%, also. It's very similar to celiac disease in patients, especially with IBS-D. The issue is that testing's not available for this in the United States. There is a serum C4 test and then a nuclear medicine test called SeHCAT, and we don't have those available.

This was a North American guideline. Also, there's been not a lot of studies showing that bile acid sequestrants are helpful, necessarily, in the IBS-D populations. There were some studies, but there wasn't a large amount compared to placebo with long duration.

Therefore, because of lack of data at this point in time, we did not recommend bile acid sequestrants be used in patients with IBS-D.

Dr. Lacy:  Again, they may work in individual patients. We just don't have those large, randomized controlled trials like we did, as you mentioned, for plecanatide and linaclotide. Let's think about the TARGET I, TARGET II, and TARGET III studies, 3 large studies looking at the value of rifaximin for the treatment of IBS-D symptoms. How do you use rifaximin in your practices?

Dr. Moshiree:  Rifaximin, based on these studies of course, a third of the patients can have resolution of their IBS-D symptoms, so that's a fantastic outcome. A third of the patients we may never have to see because they're cured in a way. Although, again, this is a chronic condition. The drug has great safety.

In my population, our recommendation was a strong recommendation based on a moderate level of evidence. The retreatment is based on TARGET III studies, where these are patients that benefited initially, but then had recurrence of symptoms. Then, they were placed in this TARGET III trial where they were retreated. Again, there was improvement of their global symptoms of IBS.

In my practice, with the initiation of the low FODMAP diet, this is something I do very quickly thereafter because it's a safe drug. It's 95% bioavailable in the gut. There's not a lot of other side effects associated with this drug. It is expensive, so the only issue with the drug is that for people with insurances where this is not authorized, it can be an issue.

Taken with a 2-week course, again, a third of the patients not having to be seen by a physician or a practitioner, and having resolution of their symptoms is great. I use that in IBS-D population often.

Dr. Lacy:  Wonderful. Great for our listeners. Safe and very effective for many patients. Alosetron, a lot of our listeners may have forgotten about that. It's a 5-HT3 antagonist. It slows the GI tract, helps urgency and diarrhea, and can be very effective at treating IBS-D symptoms in women who have failed standard therapy, but it's not widely used. How do you use this medication in your practice?

Dr. Moshiree:  This is a drug that was around at same time as tegaserod. They pretty much came around the same time. The issues with alosetron were ischemic colitis. There was a very low risk of ischemic colitis after review of several meta-analyses that was done later on. The FDA regulated it, so there was a REMS certification that was necessary for prescribing the drug. You had to put these blue stickers on the prescriptions when you ordered them. You entered a contract with the patient. Patient had to sign a consent form saying that if they have constipation or development of abdominal pain, that they are to stop the drug, and that they know the risk of ischemic colitis exists. That's now been taken away.

In my practice, I continued to use the drug the entire time, even with the consent form because I found it to be effective. It is recommended in our guideline, although the recommendation is a low-level recommendation. In patients with moderate or severe IBS-D who are suffering with abdominal pain and diarrhea, it can be effective.

The dose starts at 0.5 mg. Usually I'll start at the lowest dose, 0.5 mg once a day, and then I'll increase it to 0.5 twice a day if they have improvement in their symptoms. In other patients, they may have to be on 1 mg instead of the 0.5 mg. I tell them to watch out for constipation, of course, worsening. If that occurs, you stop the drug.

Development of ischemic colitis...If they have other risk factors for developing ischemic colitis, this is not the drug for that patient.

Dr. Lacy:  Yes, a good teaching point. It is underused and can be very effective. For our listeners, don't forget that. How many of our patients used herbal products, including peppermint oil? What's your view on herbal products and alternative therapies like peppermint?

Dr. Moshiree:   I'm a big fan. I come from a Asian background where I'm pretty sure I had turmeric with every food I've [laughs] ever ingested, and then curcumin. Ginger has been in every [laughs] concoction, cinnamon, etc. There's a large meta-analysis that was done looking at 12 studies where peppermint was used.

Peppermint itself has l-menthol which blocks calcium channels. That relaxes smooth muscle, so there's definitely a physiologic reason. Recently, we've also found that it modulates the transient receptor voltage channels that help with this visceral hypersensitivity and sensation.

When we reviewed those 12 studies and the meta-analysis that was recently published, there was a lot of bias. The studies were heterogeneous, but enteric-coated peppermint actually can be helpful with the global symptoms of IBS. Now, that's the only herb so far that has been shown to help with symptoms of IBS. The other ones haven't been rigorously studied.

Some of it is probably that herbs, to go through this rigorous, randomized control trials, are much harder to study because of funding.

Dr. Lacy:  Yes, absolutely. Baha, lastly, the guidelines recommend the use of neuromodulators to treat IBS symptoms. In particular, tricyclic antidepressants. Can you tell our listeners which agent or agents you prefer and why? How do you use these agents?

Dr. Moshiree:  Tricyclic antidepressants are the neuromodulators that have the most well-designed studies. Specifically, amitriptyline, desipramine, are agents that have been studied. There's 12 randomized control trials with that as well. Their use is mainly in IBS with diarrhea, but of course, they can also be used in mixed-type IBS.

Mixed-type IBS is oftentimes left out of these studies because the symptoms can be exacerbated by whether you give them constipation drugs, or drugs that affect diarrhea since those patients alternate. These drugs work on norepinephrine and dopamine, but they also have anticholinergic mechanisms, which accounts for the dry mouth and the constipation effects.

I use the tricyclic antidepressants such as nortriptyline or desipramine that have less of those acetylcholine side effects. Those are my favorites. I usually start them a low dose of 25 milligrams and then I increase them up to 75 milligrams or higher.

We do give it to them for a longer period of time like 6 months, because they start having an effect at about 4 to 6 weeks. You do want to increase them if the patient hasn't had a bad side effect and if they're having improvement.

Usually I tell patients you're not going to see an improvement in a week or 2 like you may on a laxative, but the symptoms of pain should start improving after a month or 6 weeks. It's important for them to see us so that we can increase the dosage on their tricyclics.

These were definitely recommended based on the guidelines. The number needed to treat was about 4 for tricyclic antidepressants in IBS.

Dr. Lacy:  These can be really effective agents. For our listeners, get comfortable with 1 or 2, know the ins and outs, and incorporate them into your practice.

Baha, this has been an amazing discussion. Thank you. You've provided a wealth of information to our listeners. Thank you so much. Any last comments for our listeners?

Dr. Moshiree:  Yes, absolutely. Of course, we didn't talk about the psychological interventions that can be done by our GI psychologists in patients with irritable bowel syndrome. A multidisciplinary approach can be incorporated to many practices.

I do understand that in a private practice module-type of hybrid practice that I am in, it is difficult to get dieticians and GI psychologists, but they are definitely out there.

For the IBS population, having them as part of your team is really important to helping these patients. Avoiding too many diagnostic testings is probably better for our health care system, but also better for each of our individual patients.

Having confidence in the diagnosis of IBS is really important. Realizing that subtyping patients will help guide treatment is also very important. Listen to the patients. These are patients that require more time, I would say, than perhaps others that have a definite organic cause to their disease.

Finding out the patient's stressors, other comorbidities, effectively communicating with them is really important in patients with irritable bowel syndrome. Hopefully these have been helpful guides here.

Dr. Lacy:  Baha, once again, on behalf of the GI Learning Network and behalf of our listeners, thank you so much for this great educational podcast. We can't thank you enough.

Dr. Moshiree:  Thank you, Brian. This was great. Thank you.