Gut Check: Drs Brian Lacy and Satish Rao on Constipation

Host Brian Lacy, MD, reviews the diagnosis and treatment of acute and chronic constipation with Dr Satish Rao.

Brian Lacy, MD, is a professor of medicine at the Mayo Clinic in Jacksonville, Florida. Satish Rao, MD, is professor of medicine, chief of gastroenterology, and director of the Digestive Health Clinical Research Center at WellStar MCG Health, Augusta University, in Augusta, Georgia.

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, and I am absolutely delighted to be speaking today with Dr. Satish Rao, professor of medicine, chief of gastroenterology, and director of the Digestive Health Clinical Research Center at WellStar MCG Health, Augusta University, in Augusta, Georgia.

Our topic today is one that routinely comes up in both GI clinics and primary care chronic constipation, and we'll focus much of our discussion today on recent advances in this field.

So Dr. Rao, welcome. Constipation is a common problem for many patients, but it comes in a variety of forms, right? IBS with constipation and occasional constipation to name just a few. So for our listeners today, when health care providers initiate an evaluation for a patient with symptoms of constipation, what are the most common categories of constipation that need to be considered?

Dr Rao: Hi, Brian. What a wonderful way to begin this interesting dialogue with you. It's always a pleasure to be back on this learning network and I'm very pleased that you are focusing on this very important topic. As you know, constipation affects between 15 to 20% of the US population and globally. And it is not only a common symptom, but often misunderstood, misdiagnosed, miscategorized, and misevaluated across the board. So it is so much more topical to discuss this and share some of our recent knowledge and thoughts in this area.

And you really started off on a very important question asking, what are the common categories that are really thought of when practitioners see these patients? I mean, first and foremost, as I say, is practitioners don't even recognize very often that these symptoms exist, which is interesting. But nonetheless, the critical question that I always like to bring up is, you know, it is important to have some kind of a working definition or working categorization of these patients. And generally, I look upon constipation as either occasional constipation or more chronic constipation.  Mostly, we see as specialists in gastroenterology, patients with chronic constipation. But in general, I think occasional constipation is probably much, much more common, but less well recognized and so on.

Now, in the chronic constipation arena, there is what I always call primary constipation and then there is secondary constipation. Primary meaning that there is a significant dysfunction, primarily in the gut, particularly colon or the rectum. Something is not working properly in the colon or the rectum that is then leading to constipation symptoms.

And secondary, meaning that there is a dysfunction in the gut, but something outside the gut is actually triggering this. I give you an example. Some people, for example, people who take pain medications such as opioids or someone who's anemic, may be placed on iron tablets. So these are potentially drugs that are then indirectly slowing gut motility, which then leads to constipation. So that's the kind of secondary reason why people get constipated. That's how I look upon this, occasional primary or secondary constipation.

Dr Lacy: Wonderful, thank you. That's such a great perspective. And I like your comment, I think so many health care providers are so busy that they just don't have time to ask, but as you mentioned, this affects 15 % of the population. That's 1 in 6 to 1 in 7 people coming through your office.

So that you and I and our listeners all speak the same language, when you say chronic constipation, how do you really define that? Is there one definition that you use? What are your criteria?

Dr Rao: So I think this is one area where the Rome Foundation over many years of research have really helped us in crystallizing the thought process quite a bit because years ago, most physicians generally or health care providers would define constipation based on symptom frequency. In other words, the first question that anybody would ask is, oh, how often do you have a bowel movement? And if the patient says, oh, once a week, oh, that sounds like constipation.

On the other hand, if the patient said, oh, once a day or once every other day, then they would really start questioning, is this really constipation? So this was the kind of the prevailing myth that constipation was primarily defined as a disorder of decreased stool frequency.  But that myth was really taken on by the Rome Foundation, which really helped to crystallize the many facets and many symptoms that together constitute constipation. In other words, constipation is not a single-symptom disorder, but is a multisymptomatic disorder.

And so let me elaborate on those symptoms that are quite common, but yet not always touched upon or focused by most people. I just talked about stool frequency, but there are other symptoms such as excessive straining having a bowel movement, a feeling of incomplete evacuation, use of digital maneuvers to help or facilitate a bowel movement, a feeling of blockage, and importantly the frequent passage of hard pellet-like stools. So there are roughly 6 symptoms that we now use to help us more efficiently diagnose chronic constipation. And in general, and you asked the question, how do I diagnose if a patient reports at least two of these symptoms and if they have been present with, let's say, at least 25 % of more of bowel movement and occurring for up to 3 months or longer, then I would really call that patient suffering with chronic constipation.

Dr Lacy: Such a great teaching point, Satish. Don't just ask about stool frequency. Ask about those others. Really important symptoms of straining, incomplete evacuation, hard stools, and using manual maneuvers. Because then, otherwise you may miss a lot of people, you can help.

As we shift gears, you were part of a group that really wrote a really nice article, defining occasional constipation, kind of bringing it to the forefront and defining it. So how do you define occasional constipation? What are your criteria?

Dr Rao: So great question, actually. People have recognized, in fact, many of us have even experienced these kind of symptoms. You know, when we travel, we go to a strange place or a work schedule has become a little hectic. We've been not paying attention to a usual work-life balance, et cetera, et cetera. One thing that takes a hit is our intrinsic body biorhythm. And bowel movement is just one of those intrinsic biorhythms that can take a hit if we don't sleep, if we don't eat, and if we are doing activities that are outside the usual normal boundaries. So in that sense, many people suffer with occasional constipation. Many of them will probably don't even visit a physician, but may either talk to a family member or go to a pharmacist or talk to a pharmacist.

So, to try and really help better understand this problem, a group of experts, an international group of experts, came together and they helped define this problem. And what we said—and we had some literature that we reviewed and some of us have participated in some of those working studies as well—what we said is if a patient has intermittent or occasional alteration in bowel habit without any warning signs or alarm features—and I'll describe them in a minute—but bothersome enough that they feel that they may need some change, such as either changing their lifestyle, changing their diet, or needing to use some over the counter laxatives or agents to restore a bowel habit, then that condition is what we would say is constipation. So here, there is no period that this could be just a few days of change in bowel habit, doesn't have to be months and so on. But the critical thing is these patients experiencing these symptoms should not have any alarming features, such as blood in their stool or have lost some weight recently or are experiencing abdominal pain or have a history or a family history of colon cancer or have started some new medications. If any of these potential features are present, then that individual who's experiencing these kind of occasional constipation symptoms should first consult a physician before we really make a diagnosis of occasional constipation.

Dr Lacy: And Satish, when we think about patients with occasional constipation, is there a high-risk group? Is it just older women or younger men?

Dr Rao: No, I think a great question. I think it's across the board. Men, women, older or younger folks, everybody seems to experience this problem. In fact, just to add to what I just said, a very nice study was done in Mexico fairly recently and presented at our national meeting, I think this year, where they took the definition, this new definition about 2, 3 years ago, we published that, and they use that as the basis for a community-wide survey of patients with symptoms of constipation. And they found that the prevalence was about 30% of occasional constipation as opposed to the prevalence of chronic constipation, which was around 10 -12%. So this was a large community study done using the definitions. And so there was clearly a  reaffirmation that A, the problem exists; and B, it can be identified using some of the criteria that we developed. And the prevalence, interestingly, was fairly similar across gender.

Dr Lacy: And so when we think about these patients with occasional constipation, and if you were to see somebody in your office who reported episodes of occasional constipation over the last year or two. Is any testing necessary for these patients or are symptoms enough and you just initiate therapy?

Dr Rao: I think these symptoms are usually adequate alongside the absence of warning features. Once there are no warning features and These are occasional disturbances in bowel habit or difficulty with stool passage. I think that is enough to diagnose occasional constipation. And usually once that is done, then the best step forward is without testing to proceed with symptomatic management. And this can be changes in lifestyle, including perhaps more fiber in their diet, more ritualizing their bowel habit, more regularizing their eating habits, and a number of over the counter preparations. You know, we have recently, fruit products, for example, have become very popular. So kiwi fruit, prunes, mango, I mean, these are fruit products that that we can, we can advise these patients, or simple over the counter laxatives, magnesium or senna products, et cetera. So these are all very appropriate agents for people to use. Often short -term, people are looking at maybe a 2 -week treatment or maybe a 4-weeks treatment. And I think their symptoms should completely resolve with that kind of approach.  If symptoms don't resolve, then I think there is a cause for concern.

Dr Lacy: You gave such a nice overview of treatment options for occasional constipation including fiber and foods which we can sometimes use foods as medication and over-the -counter agents. For our listeners who are patients and our listeners who are health care providers, are there any head-to-head comparison studies showing that you should use A first always then B then C?

Dr Rao: In the occasional constipation arena there are very few studies. There have been some studies of fiber and some products but not really in a very good way. Even in the other population studies I don’t think there is a clear preferential characterization of these agents. But in the last decade what we've seen is some studies in the chronic constipation arena where there have been some head-to-head studies. For example, a study in Japan compared magnesium with senna, and showed that when compared to placebo, both magnesium and senna were better. There were slightly higher side effects, I think, with senna, but overall, they were both equally beneficial in the study. Likewise, the study on kiwi fruit, which again, a couple of studies have been done, and both of them showed that having eating 2 kiwi fruits a day is better.

So I think these are some randomized control studies recently coming through showing that a number of this over the counter, easily available or I could say over the grocery product list that actually can be very helpful in managing simple and occasional constipation.

Dr Lacy: Great, sounds like a perfect opportunity for the patient and health care provider to discuss kind of benefits of these agents, including foods and side effects and maybe even costs. And that was such a perfect segue, and similarly, I want you to think a little bit about chronic constipation. And can you tell us about any big advances in terms of medications for the treatment of chronic constipation?

Dr Rao: Yes, I think, thanks, Brian. There have been some, you know, some really significant advances in the field of chronic constipation. You know, for the first time, we have, let's say over the decade, we have several FDA approved agents going back to 2006, you know, lubiprostone, which is a chloride channel activator, CLC2 activator, which was approved by the FDA for treatment of chronic constipation. We've had one or two serotonin compounds, for example, tegaserod, but then it was withdrawn by the FDA for its treatment. But more recently, maybe about 5 years ago, prucalapride, which is a serotonin agonist. In other words, it specifically works on the one type of serotonin receptor, 5HD4 receptor in the gut and these receptors are present to a slightly greater extent in the colon than in the upper gut, nonetheless they are present throughout the gut and they activate these receptors. Activation of the serotonin receptors leads to increased motility, increased peristalsis in the gut. So that's another agent that has been approved based on control clinical trials.

And then we have 2 other very interesting compounds which are called GCC agonist or guanlate cyclase C agonist. The first one was linaclotide, approved somewhere around 2012, about a decade ago, and then somewhere about 7 years ago another sister compound called plecanatide. Both of these act on the guanlate cyclase C mechanism and they all induced secretion in the gut which in turn leads to bowel distention and laxation.

So these are some of the agents that are all FDA approved for the treatment of chronic constipation. One agent that I did not mention but is very popular and commonly used is polyethylene glycol, the common trade name is Miralax and so on. And this one has been studied for short duration primarily if there's a period only for a 2-week course of treatment. There are some longer-term studies both in the US and outside the US and is another agent that is commonly prescribed for the management of chronic constipation. A fairly well tolerated with minimal side effects.

Dr Lacy: Satish, shifting gears a little bit, you played a key role in a prospective study of the vibrating capsule for patients with chronic constipation. Kind of what led to the development of that? What were you thinking and what were the results of that prospective study published in Gastroenterology?

Dr Rao: Oh great, that's a wonderful question. So before I answer specifically about the vibrating capsule, I'm glad you asked this question because I think there has been a growing interest, let me put it this way, of nonpharmacologic therapeutic approaches for management of chronic constipation, either because patients have experienced intolerable side effects, patients are concerned about the use of chemicals, or there are drug-drug interactions and so on, multiple other reasons. So there has been generally a push or a need for development of nonpharmacologic approaches, approaches using treatments that have a more selective effect primarily in the gut and primarily in the colon.

So over the last decade there has been a resurgence of interest and just to name a few treatments--you've actually mentioned the vibrating capsule that I'm going to talk about in a minute. Other treatments that have been tried are things like acupuncture—right the good old, you know, Chinese treatment approach people have done—and the good thing is the last few years there have been some interesting randomized control trials of acupuncture. Another interesting treatment has been interferential therapy where they wear like a belt-like device or electrodes on the belly front and the back and they pass electric current between the front and the back electrodes and where those energies meet that interferential current that is generated can trigger bowel peristalsis and there have been some clinical trials on that. So there have been you know some interesting developments of either external treatment to kind of jumpstart the colon if you like or internal treatments such as use of this vibrating capsule.

So a company out in Israel came up with this idea that—you know it's the same pretty much the same technology that most of us are familiar with, which is the vibrations that we see in our cell phones. You know, whenever we put the cell phone on that vibrating mode, it's pretty much the same technology. And it is very benign, as we know, cell phone vibrations are very benign. But that same technology has now been incorporated into a slim capsule. So what is interesting is that when a patient takes the capsule, several hours after ingestion it is timed roughly about the same time a capsule will take to get to the colon. This capsule becomes activated and it roughly vibrates about 3 times a minute and continues vibration for up to 2 hours and then goes to sleep, wakes up 6 hours later and The gain starts vibrating at 3 times a minute for a couple more hours and then goes off to sleep again. And maybe if the capsule is still in the body, may even vibrate a third time, but typically twice. And that's the amount of battery power, et cetera. All of this has been very cleverly packed into a single capsule called the vibrating capsule.

So that was the technology that was developed. But then the next question came is, how do we optimally deliver this? What is the best number of capsules to give? And the company actually took another 8 years to really refine their testing methodology and all of this stuff, eventually culminating in a large randomized control trial that was done just before the onset of COVID. And so Nonetheless, the study was completed and I had the pleasure of being one of the lead authors on that study and it was published in our number 1 GI journal.

What we found in that study in a nutshell was about 300 or 30 patients were randomized to either sham capsule or the vibrating capsule and about 37% of patients who received the vibrating capsule met what we call as a primary outcome measure. In other words, they had one or more increase in number of complete spontaneous bowel movements as compared to about 23%. Sorry, it was 39 % compared to about nearly 20% with the sham capsule. They also used another measure where they looked at 2 or more increase of complete spontaneous bowel movements per week and that was about 23% in the vibrating capsule arm and about 11.5% in the sham arm.

So these data were compelling enough for the FDA to permit approval and it is now available in the US now for about 18 months or so where you can actually prescribe this. And the way people will use this is it is recommended by the FDA that patients take one of these capsules 5 times a week. So it's not every day and it's not more than one a day. It's just once at night time, 5 nights out of 7 nights. And then, you know, many people are experiencing significant benefit.

The nice thing about this, at least in the clinical trials and also my personal experience thereafter, has been the very minimal side effects. Certainly no diarrhea with this agent compared to other drugs that we prescribe. The only effect that patients have described, which we saw in the clinical trial, about 11% of patients experienced a vibrating sensation. It was not significant enough that they did not want to continue with the study, or nobody withdrew from the study because of the vibrating sensation. It was a little nuisance but they were okay with it because it was not continuous; it vibrates for a couple of hours and then stops.

Dr Lacy: Well, fascinating technology and thank you for educating our listeners about that, many of whom may not have had time to read that article yet, published in Gastroenterology.

So as we start to wind down here, Satish, let's just focus for a minute on IBS with constipation, one of the other big categories for constipation. And a medication with a different mechanism of action is now available, and that's called tenapanor. What is this and how does it work?

Dr Rao: I’m glad you asked me about that. This is a very interesting novel compound. So,tenapanor is a sodium hydrogen exchanger 3 blocker. The gut, as we know, you know, we put in a lot of things in the gut. We put in food, we put in salt, we put in fluids, and there are specific channels through which each of these different molecules are absorbed. So one channel for sodium absorption is this NHE3 or a sodium exchanger channel, which selectively absorbs sodium into the gut.

Tenapanor is a blocker of that particular channel. So when you block sodium absorption, sodium will stay inside the gut lumen. And sodium, when it stays on the gut lumen, it draws water into the gut lumen. And this process leads to fluid accumulation in the gut, which then leads to gut distention. And when the gut becomes distended, the gut has an automatic process of inducing what's called as peristalsis, and it moves its contents further downstream. So that is how tenapanor works in improving constipation symptoms.

But what you nicely said is what about the IBS? The IBS patients are an interesting group of constipated patients where they not only have constipation symptoms but they also have pain and discomfort as equally bothersome and troubling symptoms. So what is interesting about this compound is animal experiments have shown 2 other interesting effects. One, it decreases pain firing from the gut wall and second, it improves intestinal permeability in the gut epithelium. So there are 2 additional benefits and these two mechanisms have been shown to play a key role in causing pain in patients with IBS. Particularly, the IBS patients have what we call as hypersensitivity. Their gut is too sensitive to everything. So by kind of numbing the gut, if you like, you can relieve their pain and also relieve their constipation with this compound. So an interesting way of really categorizing this drug effect is what we call as a retainagog. In other words, it kind of retains fluid in the gut.

And in clinical trials, something like 36% of patients who were given this drug as opposed to 23 patients who received placebo showed significant benefit that is improvement both in pain and in constipation symptoms. Just pain alone or constipation, I think about 49, 45 % of patients got better.

Dr Lacy: Wow, once again, lots of great advances in the field. Satish, this has been a wonderful conversation. I really can't thank you enough. Any last thoughts for our listeners?

Dr Rao: No, I think this was a wonderful discussion, Brian. Just to finish up by adding that, you know, we discussed about chronic constipation, we discussed occasional constipation, we discussed IBS with constipation. I briefly mentioned secondary constipation such as drugs or patients with neurological diseases such as Parkinson's disease or sometimes pregnancy, etc.

But one area we didn't have much time—and I'm sure we can find another time—is to talk about pelvic floor disorders such as what we call is dysenergic defecation, which is another important facet of this constipation problem, which affects another half of the population with chronic constipation symptoms. And these folks may not respond to all the various important advances that we talked about, and they may need another treatment, which is really biofeedback therapy. And I'm sure one day we'll have a little bit more time to talk about that, but I just wanted to mention that just so that patients and listeners and our physician colleagues have a more, more complete understanding of the various causes of constipation and treatment options.

Dr Lacy: All right. Well, you just heard coming attractions from Dr. Satish Rao, and we'll hear more in the future. So, Satish, again, thank you so very much. 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, and you have been listening to Gut Check, a podcast from the Gastroenterology Learning Network. Our guest today was Dr. Satish Rao from Augusta University in Augusta, Georgia. I hope you found this just as enjoyable as I did, and I look forward to having you join us for future Gut Check podcasts. Stay well.