The Pharmacological Management of Constipation

Professor Satish Rao, MD is the J. Harold Harrison, MD, Distinguished University Chair in Gastroenterology. Dr. Rao is also founding Director of the Digestive Health Center and Clinical Research Center, and tenured Director and Professor of Medicine. His research interests in Neurogastroenterology/Motility have focused on gaining mechanistic insights, developing novel diagnostic tools and pioneering innovative treatments for constipation, dyssynergic defecation, fecal incontinence, IBS, food intolerance, gas and bloating and small intestinal bacterial and fungal overgrowth (SIBO/SIFO) and visceral pain. His latest invention translumbosacral neuromodulation therapy (TNT) is revolutionizing treatment for fecal incontinence.

As a gastroenterologist, with a focus on research that includes pathophysiological treatment of IBS and constipation as the primary objective, how prevalent is it in your current practice?

Dr. Rao: It is a pleasure to discuss a topic very close to my heart. It is a very important but often neglected topic, and very many times people go to pharmacies, over-the-counter, or their grandmothers, seeking treatment for constipation, whereas, with all the advances today, they should be coming to us, gastroenterologists, as the primary source for really managing this problem.

Constipation is very common. It all depends, to some extent, on how we define it. But if we define it based on some more popular criteria, such as those supported by the Rome Foundation criteria, the global prevalence, is between 10% to 15%. As you can see millions of Americans suffer with this problem, and almost all AGA members would have seen hundreds of these patients in the course of their practice every year. So, it is highly prevalent.

The term constipation is misunderstood by many people. Different people have different names, different people have different definitions and different criteria. For years, most physicians and most textbooks equated constipation to infrequent bowel movements. That logic has changed dramatically in the last 10 to 15 years, where we now recognize constipation as not only infrequent bowel movement but, more commonly, difficulty with bowel movement. This difficulty with bowel movement has been the missing link as we were all focused on infrequent bowel movement. We now recognize that constipation means one of six things.

What are those six things that tell us it’s constipation? One, there’s excessive straining to have a bowel movement; two after having had a bowel movement, you're left with a feeling of incomplete evacuation; three, the stools are hard and difficult to pass. We have a very famous scale, called the Bristol Stool Form Scale. If anybody takes the time to look at the scale, if your stool form happens to be 1, 2, or 3, then you're more likely to be constipated; four, a patient has to use digital maneuvers or some kind of support to try and evacuate stool; five, a patient reports a sensation of blockage at the time of bowel movement repeatedly, and at least with 25% of bowel movements; and six, stool frequency of less than three bowel movements per week.

In order to diagnose constipation, if a patient has any two of these symptoms, for 25% of bowel movements over a period of three to six months, then that individual should be considered as having chronic constipation.

When is pharmacological management of constipation appropriate? And what diagnostic approach do you usually take to determine treatment?

Dr. Rao: I usually take a very detailed history from these patients. One of the things we have recognized,  recently, is how inadequate our history has become, not necessarily from a lack of asking questions, but it seems to be a multifactorial process. We tested this in a prospective study showing that only 30% of the time were patients history correct in letting us know why they came to the clinic. The same patient who answered a questionnaire about their symptoms, when they keep a diary for one week, there's only 30% of the time there is concordance; 70% of the time the story is different.

Hence, the first step really is to get an accurate story about your patient with constipation. Fortunately, there are some digital apps that are available, a constipation stool diary app, and there is a MyGiHealth app, et cetera. People can use these apps or they can keep a paper diary. The next step would be to determine what may be mechanistically going wrong. These two steps will guide your management approach.

We have some simple tests that we can do. One is called a colon transit study, where we measure the speed at which stool goes through the colon. And we have two tests that are commonly used. One is called a Sitz marker test. The patient swallows the capsule which has 24 plastic rings. And then they take it on day one. They get an X-ray on day six, which is 120 hours later, and you count how many of those markers are left behind with the X-ray. If there are more than five, it's abnormal. It says they have slow transit. In other words, lazy colon. On the other hand, if they pass most of the markers, then they don't have a lazy colon.

The second test we often do is a wireless motility capsule test, which is again a capsule they swallow. They wear a recorder for five days. And then that measures the speed at which the capsule goes through the colon. A very simple way of measuring colon speed as well. These tests tell us if you have a lazy colon.

Another test that we do is anorectal manometry. We do the test because 40%-50% of patients have pelvic floor dysfunction. And that gives us important insights mechanistically whether they have rectal hypersensitivity or whether they have a problem with evacuating stool. If they have rectal hypersensitivity and they're complaining of constipation, then it equates to irritable bowel syndrome with constipation. That's how we pick up that category of constipation.

The other category I mentioned earlier, lazy colon, is slow transit constipation. And the third category we often see is called dyssynergic defecation, where they are unable to evacuate stool in a timely, orderly fashion. And that is the third group of constipation. Use these tests to help you diagnose which kind of constipation a patient has. That will then guide towards appropriate management.

Is there a higher frequency in the need for pharmacological management of constipation? And is it in any particular patient, for instance, such as older adults, the elderly, or those that may be critically ill, or any other demographic?

Dr. Rao: In terms of managing the constipation itself, many times patients will go to the drugstore or talk to a pharmacist and start taking some over-the-counter preparations.

Until recently, there hasn’t been any good study to tell us which one works, which preparation works. But we recently published a systematic review of which I had the pleasure of serving as the first author, where we looked at the 30-year data on over-the-counter treatments. We found that there is very good evidence to support polyethylene glycol, PEG, as grade A, recommendation.

We also found good evidence for senna, and  for magnesium. These three compounds had good evidence. Whereas, for other over-the-counter preparations, such as fiber supplements, there are some fruit-based supplements that are now available, lactulose and so on, the evidence was second grade.

With regards to prescriptions, a drug that is approved is linaclotide, which is approved at a dose of 145 micrograms a day in a capsule form for treatment of chronic constipation. It's also approved for IBS with constipation at a higher dose of 290 micrograms a day. We also have plecanatide 3mg tablets. Both linaclotide and plecanatide, are guanylate cyclase C receptor agonists. They activate secretion through the guanylate cyclase pathway in the gut. And then, by inducing secretion, they improve constipation. Both drugs are approved for IBS-C and chronic constipation.

Then we have lubiprostone, which is a chloride channel 2 activator drug that is approved at a dose of 24 micrograms twice a day with food for treatment of chronic constipation, and 8 micrograms twice a day for treatment of IBS with constipation.

The most recent drug that was approved is called prucalopride. And this is approved at 1 to 2 milligrams a day. And this is a serotonin compound, which speeds up the gut activity including the, stomach, small bowel, and the colon. And by speeding up  gut activity, it improves constipation.

Regarding particular demographics, I find that older patients tend to be a little bit more sensitive to some drugs. Some older adults are more refractory to standard compounds, which makes their management a little bit more challenging. We have to really titrate the dose very carefully.

The critically ill group is a little bit more challenging. Often, it's acute constipation or they're in ICU settings and there the management becomes a little bit more complex. One component of that critically ill group-- and of course, you can also see them in outpatient practice-- is the opioid-induced constipation, which is a category in its own right and has been recognized by the FDA. Unfortunately, one of the major side effects of opioid is constipation. It takes a toll in the gut.

Fortunately, we have a new set of drugs, called PAMORAs, or peripherally acting mu-opioid receptor antagonists. These drugs, when you take them orally, will neutralize the effect of opioids in the gut, and thereby relieve constipation without affecting the analgesic effect of opioids. Examples of these class of drugs are methylnaltrexone, naloxegol, naldemedine, etc. These are all FDA approved now for treatment of opioid-induced constipation, which is part of your critical ill or hospitalized patients, and sometimes they are really outpatients as well.

Are there risk factors?

Dr. Rao: There are several risk factors for constipation.  They include, for example, elderly, particularly people who are not very mobile for various reasons, people-- but I think the biggest risk factor that I would like to mention, emphasize, is drugs. There are many, many, many drugs that cause constipation. Opioids, as I just mentioned . Also a number of anti-hypertensive drugs. Calcium channel blockers, for example,  are constipating.

Now, iron,  heavy metals, and calcium,  are very constipating. So are anticholinergics, and antidepressants. Many antidepressants, particularly the tricyclic class,  are very constipating.

My first message to my colleagues is, when a patient is presenting to you in the clinic, the first thing I teach my students, residents, fellows, is to look at the drug list. Think about that drug as a mischief for constipation. If it is feasible and appropriate, remove the drug, or substitute the drug, as you are looking for other reasons for constipation.

Another important risk factor worth mentioning is acute constipation. Constipation in a 70-year-old person, suddenly over the last six weeks, is serious and may raise suspicion for cancer in the colon, and the need for investigation. If patients suddenly develop constipation like that, then, it is important to make sure that there is nothing blocking the colon, that is creating constipation.

One other important group is pregnancy. I did forget to mention that. Interestingly, between a quarter to a third of woman, otherwise healthy women, have never had any symptoms, however, during pregnancy they do become constipated. That's because of hormonal changes, particularly the rush of progesterone which is happening in their body. And so, they will have to be managed during their stage, and very many times they will come back to their normal lifestyle afterwards.

When it comes to the data on current and emerging treatments, what do you see in the future of pharmacological management of constipation?

Dr. Rao: I think one of the critical things in the pharmacologic management of constipation is to recognize that constipation is rarely a one-mechanism disorder. And it may be in a particular individual, but how do we know? For example, how do we know that their gut is not producing enough serotonin? And that is why they are serotonin depleted in the gut and we need to supplement them with a serotonin product, to just give you an example. We don't know that. We don't have their genetic makeup, and so on.

What I'm getting at is, constipation is a heterogenic problem, and there are multiple mechanisms that lead to it. Therefore, our current armamentarium has significantly improved in the last decade.

The first decade of the new Millennium saw significant new drugs that were introduced. The second decade has seen even more. But I think there are other compounds that are now coming up. There are sodium-hydrogen ion pump blocking drugs , and there are other mechanistic drugs . There's another drug which is available in Japan, not yet in the US, called elobixibat, which actually blocks bile acid. Normally, 95% of the bile is  reabsorbed in the colon. But if you block bile acid reabsorption and allow some bile to spill into the colon, your own bile can become a laxative in the colon.

Another important approach has been through a capsule technology, called Vibrant capsule. . I'm part of an investigative group is investigating this drug. The phase III data is not yet available but has been submitted, You take a capsule once a day, and this gently agitates the colon, and thereby stimulating the colon muscles to  move the stool, and then you evacuate. So, it is not a pharmacologic, but it is a form of a capsule device treatment .

These are some emerging treatments  just around the corner. There is kind of a belt device that you can wear around the belly, which passes a small amount of electric current in a sequential manner, to stimulate peristalsis, called electrical interference therapy.

If pharmacological management is not an option, then what's next?

Dr. Rao: Pharmacologic management works for about 50% of patients. But it doesn't work in everybody. It's not because the drug itself is not working or has side effects, instead, the issue is that the problem is not likely to be fixed by pharmacologic management.

About 40% of patients have a pelvic floor dysfunction called dyssynergic defecation.  These folks, unbeknownst to them, have learned a new process of pooping, where they are blocking their own pooping action. They're not doing it deliberately. They're totally unaware. A third of them have this problem right from childhood. 2/3 acquire this problem in adulthood. Needless to say, this problem affects 40% of patients.

So yes, you can give them medications, and that will temporarily help them. But because they cannot evacuate this stool, it will never help them permanently. These individuals are best helped by a behavioral treatment called biofeedback therapy. Hopefully in the future,  home-based biofeedback tools can become available, and that can really make this treatment more widely available to the public.

Is there anything else you'd like to add before we conclude?

Dr. Rao: My most important message to my colleagues is that constipation is a very common problem. Please take time to spend with your patients. Please use an app or a diary to record the symptoms. If at all possible, perform a digital rectal examination on all your constipated patients to identify the pelvic floor dysfunction group of patients. Manage them  appropriately with  over the counter drugs or particularly the FDA-approved pharmacotherapies. And that will work in a majority.

But when drugs don’t work or patients have predominant symptoms of difficult defecation, put on your thinking hat. Don't give up on your patients. Instead of sending them to a surgeon, which many times we rush to do, try and see what other things you can do including manometric testing and biofeedback therapy.

Professor Satish Rao, MD is the J. Harold Harrison, MD, Distinguished University Chair in Gastroenterology. Dr. Rao is also founding Director of the Digestive Health Center and Clinical Research Center, and tenured Director and Professor of Medicine. His research interests in Neurogastroenterology/Motility have focused on gaining mechanistic insights, developing novel diagnostic tools and pioneering innovative treatments for constipation, dyssynergic defecation, fecal incontinence, IBS, food intolerance, gas and bloating and small intestinal bacterial and fungal overgrowth (SIBO/SIFO) and visceral pain. His latest invention translumbosacral neuromodulation therapy (TNT) is revolutionizing treatment for fecal incontinence.

As a gastroenterologist, with a focus on research that includes pathophysiological treatment of IBS and constipation as the primary objective, how prevalent is it in your current practice?

Dr. Rao: It is a pleasure to discuss a topic very close to my heart. It is a very important but often neglected topic, and very many times people go to pharmacies, over-the-counter, or their grandmothers, seeking treatment for constipation, whereas, with all the advances today, they should be coming to us, gastroenterologists, as the primary source for really managing this problem.

Constipation is very common. It all depends, to some extent, on how we define it. But if we define it based on some more popular criteria, such as those supported by the Rome Foundation criteria, the global prevalence, is between 10% to 15%. As you can see millions of Americans suffer with this problem, and almost all AGA members would have seen hundreds of these patients in the course of their practice every year. So, it is highly prevalent.

The term constipation is misunderstood by many people. Different people have different names, different people have different definitions and different criteria. For years, most physicians and most textbooks equated constipation to infrequent bowel movements. That logic has changed dramatically in the last 10 to 15 years, where we now recognize constipation as not only infrequent bowel movement but, more commonly, difficulty with bowel movement. This difficulty with bowel movement has been the missing link as we were all focused on infrequent bowel movement. We now recognize that constipation means one of six things.

What are those six things that tell us it’s constipation? One, there’s excessive straining to have a bowel movement; two after having had a bowel movement, you're left with a feeling of incomplete evacuation; three, the stools are hard and difficult to pass. We have a very famous scale, called the Bristol Stool Form Scale. If anybody takes the time to look at the scale, if your stool form happens to be 1, 2, or 3, then you're more likely to be constipated; four, a patient has to use digital maneuvers or some kind of support to try and evacuate stool; five, a patient reports a sensation of blockage at the time of bowel movement repeatedly, and at least with 25% of bowel movements; and six, stool frequency of less than three bowel movements per week.

In order to diagnose constipation, if a patient has any two of these symptoms, for 25% of bowel movements over a period of three to six months, then that individual should be considered as having chronic constipation.

When is pharmacological management of constipation appropriate? And what diagnostic approach do you usually take to determine treatment?

Dr. Rao: I usually take a very detailed history from these patients. One of the things we have recognized,  recently, is how inadequate our history has become, not necessarily from a lack of asking questions, but it seems to be a multifactorial process. We tested this in a prospective study showing that only 30% of the time were patients history correct in letting us know why they came to the clinic. The same patient who answered a questionnaire about their symptoms, when they keep a diary for one week, there's only 30% of the time there is concordance; 70% of the time the story is different.

Hence, the first step really is to get an accurate story about your patient with constipation. Fortunately, there are some digital apps that are available, a constipation stool diary app, and there is a MyGiHealth app, et cetera. People can use these apps or they can keep a paper diary. The next step would be to determine what may be mechanistically going wrong. These two steps will guide your management approach.

We have some simple tests that we can do. One is called a colon transit study, where we measure the speed at which stool goes through the colon. And we have two tests that are commonly used. One is called a Sitz marker test. The patient swallows the capsule which has 24 plastic rings. And then they take it on day one. They get an X-ray on day six, which is 120 hours later, and you count how many of those markers are left behind with the X-ray. If there are more than five, it's abnormal. It says they have slow transit. In other words, lazy colon. On the other hand, if they pass most of the markers, then they don't have a lazy colon.

The second test we often do is a wireless motility capsule test, which is again a capsule they swallow. They wear a recorder for five days. And then that measures the speed at which the capsule goes through the colon. A very simple way of measuring colon speed as well. These tests tell us if you have a lazy colon.

Another test that we do is anorectal manometry. We do the test because 40%-50% of patients have pelvic floor dysfunction. And that gives us important insights mechanistically whether they have rectal hypersensitivity or whether they have a problem with evacuating stool. If they have rectal hypersensitivity and they're complaining of constipation, then it equates to irritable bowel syndrome with constipation. That's how we pick up that category of constipation.

The other category I mentioned earlier, lazy colon, is slow transit constipation. And the third category we often see is called dyssynergic defecation, where they are unable to evacuate stool in a timely, orderly fashion. And that is the third group of constipation. Use these tests to help you diagnose which kind of constipation a patient has. That will then guide towards appropriate management.

Is there a higher frequency in the need for pharmacological management of constipation? And is it in any particular patient, for instance, such as older adults, the elderly, or those that may be critically ill, or any other demographic?

Dr. Rao: In terms of managing the constipation itself, many times patients will go to the drugstore or talk to a pharmacist and start taking some over-the-counter preparations.

Until recently, there hasn’t been any good study to tell us which one works, which preparation works. But we recently published a systematic review of which I had the pleasure of serving as the first author, where we looked at the 30-year data on over-the-counter treatments. We found that there is very good evidence to support polyethylene glycol, PEG, as grade A, recommendation.

We also found good evidence for senna, and  for magnesium. These three compounds had good evidence. Whereas, for other over-the-counter preparations, such as fiber supplements, there are some fruit-based supplements that are now available, lactulose and so on, the evidence was second grade.

With regards to prescriptions, a drug that is approved is linaclotide, which is approved at a dose of 145 micrograms a day in a capsule form for treatment of chronic constipation. It's also approved for IBS with constipation at a higher dose of 290 micrograms a day. We also have plecanatide 3mg tablets. Both linaclotide and plecanatide, are guanylate cyclase C receptor agonists. They activate secretion through the guanylate cyclase pathway in the gut. And then, by inducing secretion, they improve constipation. Both drugs are approved for IBS-C and chronic constipation.

Then we have lubiprostone, which is a chloride channel 2 activator drug that is approved at a dose of 24 micrograms twice a day with food for treatment of chronic constipation, and 8 micrograms twice a day for treatment of IBS with constipation.

The most recent drug that was approved is called prucalopride. And this is approved at 1 to 2 milligrams a day. And this is a serotonin compound, which speeds up the gut activity including the, stomach, small bowel, and the colon. And by speeding up  gut activity, it improves constipation.

Regarding particular demographics, I find that older patients tend to be a little bit more sensitive to some drugs. Some older adults are more refractory to standard compounds, which makes their management a little bit more challenging. We have to really titrate the dose very carefully.

The critically ill group is a little bit more challenging. Often, it's acute constipation or they're in ICU settings and there the management becomes a little bit more complex. One component of that critically ill group-- and of course, you can also see them in outpatient practice-- is the opioid-induced constipation, which is a category in its own right and has been recognized by the FDA. Unfortunately, one of the major side effects of opioid is constipation. It takes a toll in the gut.

Fortunately, we have a new set of drugs, called PAMORAs, or peripherally acting mu-opioid receptor antagonists. These drugs, when you take them orally, will neutralize the effect of opioids in the gut, and thereby relieve constipation without affecting the analgesic effect of opioids. Examples of these class of drugs are methylnaltrexone, naloxegol, naldemedine, etc. These are all FDA approved now for treatment of opioid-induced constipation, which is part of your critical ill or hospitalized patients, and sometimes they are really outpatients as well.

Are there risk factors?

Dr. Rao: There are several risk factors for constipation.  They include, for example, elderly, particularly people who are not very mobile for various reasons, people-- but I think the biggest risk factor that I would like to mention, emphasize, is drugs. There are many, many, many drugs that cause constipation. Opioids, as I just mentioned . Also a number of anti-hypertensive drugs. Calcium channel blockers, for example,  are constipating.

Now, iron,  heavy metals, and calcium,  are very constipating. So are anticholinergics, and antidepressants. Many antidepressants, particularly the tricyclic class,  are very constipating.

My first message to my colleagues is, when a patient is presenting to you in the clinic, the first thing I teach my students, residents, fellows, is to look at the drug list. Think about that drug as a mischief for constipation. If it is feasible and appropriate, remove the drug, or substitute the drug, as you are looking for other reasons for constipation.

Another important risk factor worth mentioning is acute constipation. Constipation in a 70-year-old person, suddenly over the last six weeks, is serious and may raise suspicion for cancer in the colon, and the need for investigation. If patients suddenly develop constipation like that, then, it is important to make sure that there is nothing blocking the colon, that is creating constipation.

One other important group is pregnancy. I did forget to mention that. Interestingly, between a quarter to a third of woman, otherwise healthy women, have never had any symptoms, however, during pregnancy they do become constipated. That's because of hormonal changes, particularly the rush of progesterone which is happening in their body. And so, they will have to be managed during their stage, and very many times they will come back to their normal lifestyle afterwards.

When it comes to the data on current and emerging treatments, what do you see in the future of pharmacological management of constipation?

Dr. Rao: I think one of the critical things in the pharmacologic management of constipation is to recognize that constipation is rarely a one-mechanism disorder. And it may be in a particular individual, but how do we know? For example, how do we know that their gut is not producing enough serotonin? And that is why they are serotonin depleted in the gut and we need to supplement them with a serotonin product, to just give you an example. We don't know that. We don't have their genetic makeup, and so on.

What I'm getting at is, constipation is a heterogenic problem, and there are multiple mechanisms that lead to it. Therefore, our current armamentarium has significantly improved in the last decade.

The first decade of the new Millennium saw significant new drugs that were introduced. The second decade has seen even more. But I think there are other compounds that are now coming up. There are sodium-hydrogen ion pump blocking drugs , and there are other mechanistic drugs . There's another drug which is available in Japan, not yet in the US, called elobixibat, which actually blocks bile acid. Normally, 95% of the bile is  reabsorbed in the colon. But if you block bile acid reabsorption and allow some bile to spill into the colon, your own bile can become a laxative in the colon.

Another important approach has been through a capsule technology, called Vibrant capsule. . I'm part of an investigative group is investigating this drug. The phase III data is not yet available but has been submitted, You take a capsule once a day, and this gently agitates the colon, and thereby stimulating the colon muscles to  move the stool, and then you evacuate. So, it is not a pharmacologic, but it is a form of a capsule device treatment .

These are some emerging treatments  just around the corner. There is kind of a belt device that you can wear around the belly, which passes a small amount of electric current in a sequential manner, to stimulate peristalsis, called electrical interference therapy.

If pharmacological management is not an option, then what's next?

Dr. Rao: Pharmacologic management works for about 50% of patients. But it doesn't work in everybody. It's not because the drug itself is not working or has side effects, instead, the issue is that the problem is not likely to be fixed by pharmacologic management.

About 40% of patients have a pelvic floor dysfunction called dyssynergic defecation.  These folks, unbeknownst to them, have learned a new process of pooping, where they are blocking their own pooping action. They're not doing it deliberately. They're totally unaware. A third of them have this problem right from childhood. 2/3 acquire this problem in adulthood. Needless to say, this problem affects 40% of patients.

So yes, you can give them medications, and that will temporarily help them. But because they cannot evacuate this stool, it will never help them permanently. These individuals are best helped by a behavioral treatment called biofeedback therapy. Hopefully in the future,  home-based biofeedback tools can become available, and that can really make this treatment more widely available to the public.

Is there anything else you'd like to add before we conclude?

Dr. Rao: My most important message to my colleagues is that constipation is a very common problem. Please take time to spend with your patients. Please use an app or a diary to record the symptoms. If at all possible, perform a digital rectal examination on all your constipated patients to identify the pelvic floor dysfunction group of patients. Manage them  appropriately with  over the counter drugs or particularly the FDA-approved pharmacotherapies. And that will work in a majority.

But when drugs don’t work or patients have predominant symptoms of difficult defecation, put on your thinking hat. Don't give up on your patients. Instead of sending them to a surgeon, which many times we rush to do, try and see what other things you can do including manometric testing and biofeedback therapy.

Professor Satish Rao, MD is the J. Harold Harrison, MD, Distinguished University Chair in Gastroenterology. Dr. Rao is also founding Director of the Digestive Health Center and Clinical Research Center, and tenured Director and Professor of Medicine. His research interests in Neurogastroenterology/Motility have focused on gaining mechanistic insights, developing novel diagnostic tools and pioneering innovative treatments for constipation, dyssynergic defecation, fecal incontinence, IBS, food intolerance, gas and bloating and small intestinal bacterial and fungal overgrowth (SIBO/SIFO) and visceral pain. His latest invention translumbosacral neuromodulation therapy (TNT) is revolutionizing treatment for fecal incontinence.

As a gastroenterologist, with a focus on research that includes pathophysiological treatment of IBS and constipation as the primary objective, how prevalent is it in your current practice?

Dr. Rao: It is a pleasure to discuss a topic very close to my heart. It is a very important but often neglected topic, and very many times people go to pharmacies, over-the-counter, or their grandmothers, seeking treatment for constipation, whereas, with all the advances today, they should be coming to us, gastroenterologists, as the primary source for really managing this problem.

Constipation is very common. It all depends, to some extent, on how we define it. But if we define it based on some more popular criteria, such as those supported by the Rome Foundation criteria, the global prevalence, is between 10% to 15%. As you can see millions of Americans suffer with this problem, and almost all AGA members would have seen hundreds of these patients in the course of their practice every year. So, it is highly prevalent.

The term constipation is misunderstood by many people. Different people have different names, different people have different definitions and different criteria. For years, most physicians and most textbooks equated constipation to infrequent bowel movements. That logic has changed dramatically in the last 10 to 15 years, where we now recognize constipation as not only infrequent bowel movement but, more commonly, difficulty with bowel movement. This difficulty with bowel movement has been the missing link as we were all focused on infrequent bowel movement. We now recognize that constipation means one of six things.

What are those six things that tell us it’s constipation? One, there’s excessive straining to have a bowel movement; two after having had a bowel movement, you're left with a feeling of incomplete evacuation; three, the stools are hard and difficult to pass. We have a very famous scale, called the Bristol Stool Form Scale. If anybody takes the time to look at the scale, if your stool form happens to be 1, 2, or 3, then you're more likely to be constipated; four, a patient has to use digital maneuvers or some kind of support to try and evacuate stool; five, a patient reports a sensation of blockage at the time of bowel movement repeatedly, and at least with 25% of bowel movements; and six, stool frequency of less than three bowel movements per week.

In order to diagnose constipation, if a patient has any two of these symptoms, for 25% of bowel movements over a period of three to six months, then that individual should be considered as having chronic constipation.

When is pharmacological management of constipation appropriate? And what diagnostic approach do you usually take to determine treatment?

Dr. Rao: I usually take a very detailed history from these patients. One of the things we have recognized,  recently, is how inadequate our history has become, not necessarily from a lack of asking questions, but it seems to be a multifactorial process. We tested this in a prospective study showing that only 30% of the time were patients history correct in letting us know why they came to the clinic. The same patient who answered a questionnaire about their symptoms, when they keep a diary for one week, there's only 30% of the time there is concordance; 70% of the time the story is different.

Hence, the first step really is to get an accurate story about your patient with constipation. Fortunately, there are some digital apps that are available, a constipation stool diary app, and there is a MyGiHealth app, et cetera. People can use these apps or they can keep a paper diary. The next step would be to determine what may be mechanistically going wrong. These two steps will guide your management approach.

We have some simple tests that we can do. One is called a colon transit study, where we measure the speed at which stool goes through the colon. And we have two tests that are commonly used. One is called a Sitz marker test. The patient swallows the capsule which has 24 plastic rings. And then they take it on day one. They get an X-ray on day six, which is 120 hours later, and you count how many of those markers are left behind with the X-ray. If there are more than five, it's abnormal. It says they have slow transit. In other words, lazy colon. On the other hand, if they pass most of the markers, then they don't have a lazy colon.

The second test we often do is a wireless motility capsule test, which is again a capsule they swallow. They wear a recorder for five days. And then that measures the speed at which the capsule goes through the colon. A very simple way of measuring colon speed as well. These tests tell us if you have a lazy colon.

Another test that we do is anorectal manometry. We do the test because 40%-50% of patients have pelvic floor dysfunction. And that gives us important insights mechanistically whether they have rectal hypersensitivity or whether they have a problem with evacuating stool. If they have rectal hypersensitivity and they're complaining of constipation, then it equates to irritable bowel syndrome with constipation. That's how we pick up that category of constipation.

The other category I mentioned earlier, lazy colon, is slow transit constipation. And the third category we often see is called dyssynergic defecation, where they are unable to evacuate stool in a timely, orderly fashion. And that is the third group of constipation. Use these tests to help you diagnose which kind of constipation a patient has. That will then guide towards appropriate management.

Is there a higher frequency in the need for pharmacological management of constipation? And is it in any particular patient, for instance, such as older adults, the elderly, or those that may be critically ill, or any other demographic?

Dr. Rao: In terms of managing the constipation itself, many times patients will go to the drugstore or talk to a pharmacist and start taking some over-the-counter preparations.

Until recently, there hasn’t been any good study to tell us which one works, which preparation works. But we recently published a systematic review of which I had the pleasure of serving as the first author, where we looked at the 30-year data on over-the-counter treatments. We found that there is very good evidence to support polyethylene glycol, PEG, as grade A, recommendation.

We also found good evidence for senna, and  for magnesium. These three compounds had good evidence. Whereas, for other over-the-counter preparations, such as fiber supplements, there are some fruit-based supplements that are now available, lactulose and so on, the evidence was second grade.

With regards to prescriptions, a drug that is approved is linaclotide, which is approved at a dose of 145 micrograms a day in a capsule form for treatment of chronic constipation. It's also approved for IBS with constipation at a higher dose of 290 micrograms a day. We also have plecanatide 3mg tablets. Both linaclotide and plecanatide, are guanylate cyclase C receptor agonists. They activate secretion through the guanylate cyclase pathway in the gut. And then, by inducing secretion, they improve constipation. Both drugs are approved for IBS-C and chronic constipation.

Then we have lubiprostone, which is a chloride channel 2 activator drug that is approved at a dose of 24 micrograms twice a day with food for treatment of chronic constipation, and 8 micrograms twice a day for treatment of IBS with constipation.

The most recent drug that was approved is called prucalopride. And this is approved at 1 to 2 milligrams a day. And this is a serotonin compound, which speeds up the gut activity including the, stomach, small bowel, and the colon. And by speeding up  gut activity, it improves constipation.

Regarding particular demographics, I find that older patients tend to be a little bit more sensitive to some drugs. Some older adults are more refractory to standard compounds, which makes their management a little bit more challenging. We have to really titrate the dose very carefully.

The critically ill group is a little bit more challenging. Often, it's acute constipation or they're in ICU settings and there the management becomes a little bit more complex. One component of that critically ill group-- and of course, you can also see them in outpatient practice-- is the opioid-induced constipation, which is a category in its own right and has been recognized by the FDA. Unfortunately, one of the major side effects of opioid is constipation. It takes a toll in the gut.

Fortunately, we have a new set of drugs, called PAMORAs, or peripherally acting mu-opioid receptor antagonists. These drugs, when you take them orally, will neutralize the effect of opioids in the gut, and thereby relieve constipation without affecting the analgesic effect of opioids. Examples of these class of drugs are methylnaltrexone, naloxegol, naldemedine, etc. These are all FDA approved now for treatment of opioid-induced constipation, which is part of your critical ill or hospitalized patients, and sometimes they are really outpatients as well.

Are there risk factors?

Dr. Rao: There are several risk factors for constipation.  They include, for example, elderly, particularly people who are not very mobile for various reasons, people-- but I think the biggest risk factor that I would like to mention, emphasize, is drugs. There are many, many, many drugs that cause constipation. Opioids, as I just mentioned . Also a number of anti-hypertensive drugs. Calcium channel blockers, for example,  are constipating.

Now, iron,  heavy metals, and calcium,  are very constipating. So are anticholinergics, and antidepressants. Many antidepressants, particularly the tricyclic class,  are very constipating.

My first message to my colleagues is, when a patient is presenting to you in the clinic, the first thing I teach my students, residents, fellows, is to look at the drug list. Think about that drug as a mischief for constipation. If it is feasible and appropriate, remove the drug, or substitute the drug, as you are looking for other reasons for constipation.

Another important risk factor worth mentioning is acute constipation. Constipation in a 70-year-old person, suddenly over the last six weeks, is serious and may raise suspicion for cancer in the colon, and the need for investigation. If patients suddenly develop constipation like that, then, it is important to make sure that there is nothing blocking the colon, that is creating constipation.

One other important group is pregnancy. I did forget to mention that. Interestingly, between a quarter to a third of woman, otherwise healthy women, have never had any symptoms, however, during pregnancy they do become constipated. That's because of hormonal changes, particularly the rush of progesterone which is happening in their body. And so, they will have to be managed during their stage, and very many times they will come back to their normal lifestyle afterwards.

When it comes to the data on current and emerging treatments, what do you see in the future of pharmacological management of constipation?

Dr. Rao: I think one of the critical things in the pharmacologic management of constipation is to recognize that constipation is rarely a one-mechanism disorder. And it may be in a particular individual, but how do we know? For example, how do we know that their gut is not producing enough serotonin? And that is why they are serotonin depleted in the gut and we need to supplement them with a serotonin product, to just give you an example. We don't know that. We don't have their genetic makeup, and so on.

What I'm getting at is, constipation is a heterogenic problem, and there are multiple mechanisms that lead to it. Therefore, our current armamentarium has significantly improved in the last decade.

The first decade of the new Millennium saw significant new drugs that were introduced. The second decade has seen even more. But I think there are other compounds that are now coming up. There are sodium-hydrogen ion pump blocking drugs , and there are other mechanistic drugs . There's another drug which is available in Japan, not yet in the US, called elobixibat, which actually blocks bile acid. Normally, 95% of the bile is  reabsorbed in the colon. But if you block bile acid reabsorption and allow some bile to spill into the colon, your own bile can become a laxative in the colon.

Another important approach has been through a capsule technology, called Vibrant capsule. . I'm part of an investigative group is investigating this drug. The phase III data is not yet available but has been submitted, You take a capsule once a day, and this gently agitates the colon, and thereby stimulating the colon muscles to  move the stool, and then you evacuate. So, it is not a pharmacologic, but it is a form of a capsule device treatment .

These are some emerging treatments  just around the corner. There is kind of a belt device that you can wear around the belly, which passes a small amount of electric current in a sequential manner, to stimulate peristalsis, called electrical interference therapy.

If pharmacological management is not an option, then what's next?

Dr. Rao: Pharmacologic management works for about 50% of patients. But it doesn't work in everybody. It's not because the drug itself is not working or has side effects, instead, the issue is that the problem is not likely to be fixed by pharmacologic management.

About 40% of patients have a pelvic floor dysfunction called dyssynergic defecation.  These folks, unbeknownst to them, have learned a new process of pooping, where they are blocking their own pooping action. They're not doing it deliberately. They're totally unaware. A third of them have this problem right from childhood. 2/3 acquire this problem in adulthood. Needless to say, this problem affects 40% of patients.

So yes, you can give them medications, and that will temporarily help them. But because they cannot evacuate this stool, it will never help them permanently. These individuals are best helped by a behavioral treatment called biofeedback therapy. Hopefully in the future,  home-based biofeedback tools can become available, and that can really make this treatment more widely available to the public.

Is there anything else you'd like to add before we conclude?

Dr. Rao: My most important message to my colleagues is that constipation is a very common problem. Please take time to spend with your patients. Please use an app or a diary to record the symptoms. If at all possible, perform a digital rectal examination on all your constipated patients to identify the pelvic floor dysfunction group of patients. Manage them  appropriately with  over the counter drugs or particularly the FDA-approved pharmacotherapies. And that will work in a majority.

But when drugs don’t work or patients have predominant symptoms of difficult defecation, put on your thinking hat. Don't give up on your patients. Instead of sending them to a surgeon, which many times we rush to do, try and see what other things you can do including manometric testing and biofeedback therapy.