Slide Lecture with Audio
This activity is based on the combined lectures of Dr. Brooks D. Cash and Dr. Louis Kuritzky This program is available as read only and with accompanying audio.
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Slide 1:Dr. Kuritzky: Welcome to “Advances in the Diagnosis and Management of Chronic Constipation in the Primary Care Setting.”
This activity is jointly sponsored by the University of Kentucky Colleges of Pharmacy and Medicine’s C.E. office, and by Princeton CME.
Slide 2:
It is supported by an educational grant from Sucampo Pharmaceuticals, Incorporated, and Takeda Pharmaceuticals North America, Incorporated.
Slide 3: My name is Louis Kuritzky. I am a clinical assistant professor in the Department of Community Health and Family Medicine at the University of Florida in Gainesville.
I’ll be your presenter, along with Dr. Brooks Cash, who is chief of gastroenterology for the National Naval Medical Center at Bethesda, Maryland.
Please note that all faculty disclosures for this activity are included in the front of your activity booklet.
Please remember that to receive continuing education credit following the conclusion of this activity, each participant must complete the post-test and evaluation form located in the back of the activity booklet. These forms can be easily completed online for immediate receipt of credit.
Thank you again for joining us.
Slide 4: Now, to begin with our case.
Martha J. is a 62-year-old woman with Type II diabetes. She’s coming to the physician for a three-month checkup on her diabetes, and she also is troubled with hypertension, dyslipidemia, obesity and osteoarthritis of the left knee.
Slide 5: Her medications include metformin, insulin, glimeperide, and she’s achieved a reasonable fasting glucose with that, as well as A1C of 6.9.
Slide 6: The patient has a number of current medical problems. She has minimal swelling of her knee. But the pain is moderate and sometimes limits her activity, requiring her to use either non-steroidal, in the form of etodolac, or hydrocodone. She also utilizes adjunctively a combination of glucosamine and chondroitin.
Slide 7: Martha J. has other current medical problems, which include obesity, with a BMI of 31.5, despite multiple dietary consultations and failed attempts at dieting. One of the limitations she experiences is that exercise is somewhat limited, due to the osteoarthritis of her knee.
Slide 8: As we look at the portrait of the health issues for Martha J., we can easily see that hypertension, dyslipidemia, diabetes, osteoarthritis and obesity are all important figures on the map.
Slide 9: What might the traditional approach be by a clinician who sees Martha? It might begin something like this:
“Well, Martha, I see that you’re here for a diabetes re-check. How’s that glucose coming along?”
And Martha might respond, “Oh, well, doctor, you know how hard it is to keep things under control during the holidays with all the family visiting, and all.”
Slide 10: Well, when the clinician prioritizes issues in this patient encounter, we’re not at all surprised to see that the stratification goes something like this:
Diabetes, dyslipidemia and hypertension at the top. After all, those are mortal disorders, aren’t they?
Osteoarthritis and obesity somewhat below, and there is just a little slip of a piece of information about constipation on the bottom of this hierarchy that we’re going to learn a lot more about in just a couple of minutes.
There’s a better approach, though. One of the tenets of patient-centered medicine is to have the patient priorities be the clinician priorities – a shared prioritization approach.
Slide 11: So, how might the clinician elicit critical information in such a circumstance? It might go like this:
“Martha, I see you’re back here for a visit to check up with your diabetes. Before we get started on that, are there any other issues you’d like to talk about, so we can decide how to spend our time today together.”
Slide 12: Martha says, “Well, doctor, now that you mention it, there is another problem I’d like to discuss today. I’ve been having constipation for a long time, but lately it seems to be getting worse.”
“OK, Martha,” says the clinician. “Let’s talk about that some more.”
Slide 13: This re-prioritization looks like what you see on the screen now. Constipation today is Martha’s really top priority.
This is not to say that diabetes, hypertension and dyslipidemia aren’t important, but those are chronic problems, and they aren’t necessarily causing her any symptomatic deficit today.
Her obesity is a long-term problem that success has not been achieved on, and we might have to open a new avenue of investigation. But really, the most pressing problem to Martha today is her constipation.
Had the clinician just used the traditional approach, it’s unlikely that he would have discovered the problem at all.
The patient’s current medical problem that is most pressing is constipation.
Slide 14: Further inquiry informs us that she’s had this for over 10 years, despite doing the typical maneuvers of adequate fiber and improved hydration.
Martha says she has tried milk of magnesia. But the trouble is, she gets some cramping with that.
She reports that her difficulties that she describes as constipation include straining at stool, hard stool and a reduced stool frequency of only two to three bowel movements weekly.
Reassuringly, the patient did have a normal colonoscopy at age 55.
One other troubling factor for Martha is that, because she occasionally uses opioids for her knee pain, this caused her a little worse constipation subsequent to the use of the opioid.
Although one might consider that verapamil could contribute to constipation, the patient received this more than two years ago and did not notice any changes in bowel function at that time, so we think that’s an unlikely culprit. And there are no what are sometimes called “alarm signs” – weight loss, fever, bleeding or pain.
Slide 15: What therapies should be considered for patients with chronic constipation?
Slide 16: Well, I’d like to now welcome and introduce to you Dr. Cash for his presentation on chronic constipation – Dr. Cash.
Dr. Cash: Thank you Dr. Kuritzky, welcome to today’s presentation. The following information is important to primary care professionals because of the potential negative impact of this highly prevalent condition on our patients’ lives.
Slide 17: I’m going to start with the discussion of chronic constipation and present the new opportunities to improve patient quality of life and reduced healthcare resource use. And, we’re going to start first by defining chronic constipation. There are a number of different criteria that have been used to define and explain chronic constipation, but perhaps the most widely used are the Rome Three criteria.
And, the Rome Criteria were created by a group of international experts and really were designed for the use in clinical research settings to try and homogenize patients of these highly subjective functional gastrointestinal disorders of which chronic constipation is one. Other examples of functional GI disorders include dyspepsia, functional dyspepsia or irritable bowel syndrome.
Now, specifically talking about chronic constipation, the Rome committee would say that chronic constipation must include two or more of the following symptoms at least a quarter of the time with defecation. There should be straining, hard or lumpy stools, a sensation of incomplete evacuation or anorectal obstruction or blockage, or actually having to use manual maneuvers to facilitate defecation. Additionally, another criteria would be less than three defecations per week. Loose stools should rarely be present without the use of laxatives and there should be insufficient criteria for irritable bowel syndrome. Now, as I mentioned, this is a highly prevalent condition.
Slide 18: In North America, estimates ranged anywhere from two to 28 percent in terms of prevalence values. The good rule of thumb that we typically would use is somewhere between ten and 15 percent of the North American population will have symptoms that if we applied them strictly, would fulfill the Rome criteria for chronic constipation. Now certainly not all of these patients are seeking medical care and actually it’s the minority, probably ten to 15, perhaps as much as 25 percent seek medical care. But, because it is so highly prevalent there is great potential for really overloading the medical system.
The variations in these prevalence values stem from different criteria and symptom definitions that were used in these epidemiologic studies as well as different survey collection methods. But, the bottom line is that this is a highly prevalent condition affecting between 60 and 70 million people in North America.
Additionally there’s data from other countries both developed and underdeveloped , that point to similar prevalence values. And, we do know that along with other functional GI disorders there is a certain epidemiologic pattern.
Slide 19: This is a condition that is more common in females compared to males with a ratio of about two to two and a half to one.
Slide 20: It’s also a condition that is more common as patients age. Now this puts it at somewhat of a distinction between irritable bowel syndrome. We’ll talk about comparing and contrasting these two conditions a little bit later. But, as we’ll see this condition does increase in terms of prevalence along with an aging population.
Slide 21: We tend to divide constipation up into two groups, there’s primary constipation, there’s secondary constipation. Secondary constipation, is constipation secondary to another disorder, whether it’s a metabolic disorder, psychological disorder, neurological disorder, there’s another cause for the constipation that can be identified and hopefully remedied.
In terms of primary constipation we’ve broken this up into three categories, there’s slow-transit constipation, so-called colonic inertia, dyssynergic defecation, also known as pelvic floor dysfunction, and then normal-transit constipation. Many clinicians feel that irritable bowel syndrome would fit into this category, this last category although there is some contention with regards to that looking at the Rome criteria and also chronic idiopathic constipation.
Slide 22: Now, one of the main causes of secondary constipation is medication use. And, as you can see there’s a long list of medications and this is not even meant to be an all inclusive list. It’s really put here for your reference, both non-prescription as well as prescription drugs that have been associated with the symptoms of constipation.
Slide 23: Now, chronic constipation is not a highly mortal disorder, but it certainly can cause quite a bit of morbidity. There have been multiple studies that have shown that there are significant potential complications from constipation. And, one study in the U.K., up to 40 percent of elderly hospitalized patients had fecal impactions. The other things that we’ll see occasionally include obstipation or urinary or fecal incontinence, stercoral ulcerations, megacolon, even bowel perforation can occur as a result of chronic constipation.
Slide 24:
Now, there are multiple costs that are associated with this condition, both direct as well as indirect costs. So we’ll look at those costs over the next few slides.
Slide 25: In one study by Pare, 34 percent of individuals with self-reported constipation within the previous three months reported physician visits for this symptom. Significantly more common in women than men and that fits with our known epidemiologic pattern of this condition and directly associated with a number of symptoms that were present.
In terms of dollars and cents expenditures, there’s less data, but in 2001 it was estimated that $235 million were spent just on chronic constipation alone, 3 million physician visits, and you can see the breakdown there, about half were inpatient and a quarter each for emergency department and outpatient visits. When we include constipation as a secondary diagnosis, we can increase those visits by 3 million ambulatory visits and 240,000 inpatient visits. And, just in terms of expenditures for over the counter laxatives per year it’s been estimated that $800 million is spent, and that’s somewhat older data from the early 2000’s.
Slide 26: There’s been one study that looked at the cost of a tertiary care evaluation, this is somewhat of a specialized study in that number one it was very small, and number two, all of these patients were undergoing extensive diagnostic testing prior to possible colectomy for their refractory constipation symptoms. But, this study showed that the cost per patient was about $2,800 in a tertiary care setting. For every successful treatment, the total cost of care in 1994 to 1997 U.S. dollars was about 11 and a half thousand dollars. 1999 annual costs including labor, medication use and administration for constipation in nursing homes was between 22 and $2,300 per patient.
Slide 27: Now, in terms of the indirect costs, these are harder to measure and we typically will talk about quality of life and lost productivity or potential costs with regard to indirect costs associated with medical disorders. Bracco looked at this in 2004 and found that three quarters of patients with self-reported constipation reported impairment in daily activity, 60 percent impairment at work, 21 percent reported reductions in productivity and 12 percent said that they had been absent from work or school.
Slide 28: And, there have been some trends that have been noticed in terms of Medicaid population in chronic constipation. These data from a recent gastroenterologic meeting in Washington D.C. in which these authors looked at 20 percent of a random sample of the California Medicaid population between 1995 and 2003. The costs per patient for one year were calculated from paid claims as well as the following categories, outpatient care, inpatient care, prescriptions plus available OTC agents and long-term care.
You can see quite clearly that in several of these categories including outpatient as well as treatments in long-term care there were significant increases in the cost of care associated with this condition. And, we know from multiple studies that this condition along with other functional gastrointestinal conditions can have a significant impact on quality of life.
Slide 29: In the study by Jan Irvine, it shows that patients with self-reported chronic constipation compared to patients with no functional constipation have significantly lower quality of life indexes across these various domains that really is statistically significant and clinically significant for all of these domains. What’s thought to be clinically significant in terms of an SF-36 score is a difference between the investigational group and the control group of about five and we see that in just about every domain here.
Slide 30: So the key points to make with regard to the first part of this lecture is that this is a condition that comprises multiple symptoms.
Approximately 15 percent of the U.S. population, even the North American population suffers from chronic constipation, it’s more common in women, more common in patients of increasing age. There is primary constipation as well as secondary constipation, we need to look for those secondary causes, it’s responsible for a significant healthcare expenditures in the U.S. as well as worldwide and significantly diminishes quality of life and has significant potential to decrease productivity as well.
Slide 31: This slide speaks directly to the multiplicity of symptoms that patients with chronic constipation can experience. And, remember about the Rome criteria we talked about these various symptoms. This is a study by Pare in which they ask patients what their primary and most bothersome symptoms were. And, quite clearly you can see that it’s the symptoms such as straining or hard lumpy stools or sense of obstruction that are more important to patients than the construct of having one bowel movement per day or even three bowel movements per week.
In fact, patients can have either one or two bowel movements per day. If they still have some of these other symptoms over to the left, they can still fit the criteria as having constipation.
Slide 32: I alluded to the next slide earlier as well and this is really more of a constructive slide that’s meant to imply that there can be quite a bit of overlap between irritable bowel syndrome and chronic constipation. The main differentiating factor between these two conditions is abdominal pain. Patients who have a primary complaint of abdominal pain that’s associated with a change in the form or the frequency of their stool would fall into the category of having irritable bowel syndrome. But clinically, we do see patients come into both of these categories at different points in time.
Slide 33: We talked a little bit about the sub-types of chronic constipation as well and in this slide you’ll see the frequency values. The most common is normal transit constipation, pelvic floor dysfunction or defecatory disorders are less common, about 20 percent of the population with chronic constipation. Ten percent or so will have slow transit constipation and there can be some overlap between these conditions as well and unfortunately a few patients may have slow transit constipation as an addition to pelvic floor dysfunction.
Slide 34: So, when you evaluate patients it’s very important to take a good history, find out when they had the onset of their symptoms, find out what they’ve tried in terms of different therapies, what their primary symptoms are, look for secondary causes.
Slide 35: The physical exam should consist of an abdominal exam, anorectal inspection, and digital rectal examination as well.
Slide 36: We can also do laboratory testing. This has not been really shown in any randomized control trials to be terribly useful, especially in patients without alarm features, but many of us will obtain at least some baseline laboratory values. And it probably is prudent to look for hypercalcemia and thyroid dysfunction, perhaps diabetes or electrolyte abnormalities in these patients, especially if we’re going to be treating them with potential osmotic laxatives and we’ll get into that in just a few moments.
So, diagnostic testing can be valuable in patients not particularly shown to have a high yield in patients without alarm features, but many of us will do that.
Slide 37: What about colonoscopy, is it indicated? Well, there are two different positions put forth by several of our GI Professional societies, the American Gastro Association indicates that structural evaluation for constipation is appropriate whereas the American Society for Gastrointestinal Endoscopy has really the opposite take, they say constipation is not included as an indication for colonoscopy.
Slide 38: So, it’s really dealer’s choice and that is an individualized decision that you’ll need to make with every patient. There are other investigations the gastroenterologists in a more specialized setting may perhaps do such as colonic transit studies, anorectal manometry testing, defecography or functional MRI or perhaps even colonic manometry.
Slide 39: Shown is an example of a classic colonic transit study, this can be done with radio-opaque markers that are ingested as a pill and then followed with a KUB or abdominal film five days later. There are a number of different recipes, you can also do this with scintigraphy.
And you can see on the panel on the left, somebody who has had a collection of their radio-opaque markers in the rectal sigmoid area that may be indicative of pelvic floor dysfunction. On the right there’s somebody who’s got these radio-opaque markers that are distributed somewhat equally throughout the colon at day five and this may be more indicative of delayed colonic transit or perhaps sluggish colonic transit.
Slide 40: The next slide looks at anorectal manometry and this is really the diagnostic test that is required to diagnose pelvic floor dysfunction or pelvic floor dyssynergy. This is a balloon with a number of different transducers in the catheter that allows us to measure the sphincter pressure that patients are able to generate, and we all can also measure things like compliance and sensation and really should be the test of choice when we’re diagnosing pelvic floor dysfunction.
It’s also one of the ways that we deliver therapy for that condition and we’ll get into that in a little bit.
Slide 41: In terms of the management goals for chronic constipation, we want to define patients’ complaints, establish realistic goals of therapy, enhance stool consistency and colonic motility and provide long-term relief from constipation and associated symptoms and hopefully at the end of the day improve the patient’s quality of life.
Slide 42: There are a number of different approaches to treating constipation including lifestyle measures, stool softeners, fiber supplementation, laxatives and enemas. And, we’ll talk a bit about many of these.
There has not been any data that supports the use of hydration increasing dietary fiber intake or even exercise or programmed bowel movements as primary therapies for chronic idiopathic constipation. That being said, I think that many patients who are non-consulters and perhaps even some that do consult may benefit from these easy first line types of therapies. And, there are other benefits that could accrue from things such as increasing dietary fiber intake or perhaps increasing exercise. So, I encourage this use, although I would not expect in a more refractory patients for these simple lifestyle measures to be terribly effective.
Slide 43: Let’s look at the stool softeners, stool softeners can take a number of different forms but primarily they have a docusate base. There have been four randomized controlled trials that have looked at stool softeners and you can see the evidence to support their use. Several trials have shown a greater stool frequency with stool softeners, several trials have not shown any improvement compared to placebo or psyllium.
Now, the American College of Gastroenterology in their task force that was published in 2005 gave stool softeners a grade B recommendation and basically said that these agents had insufficient data to allow them to make a recommendation about the efficacy of stool softeners in patients with chronic constipation.
So, we need more studies with regards to these agents, we probably are not going to see those studies in the future. And, I think largely many of us who specialize in these areas don’t feel that stool softeners are terribly helpful in patients with chronic refractory constipation symptoms.
Slide 44: What about stress management and diet changes or other agents? These have been looked at in irritable bowel syndrome, it has been shown to have some mild effect and we’ll talk a little bit more about IBS as we move on through this talk.
Slide 45: Now, there are a number of other different types of laxatives such as bulking agents, osmotic laxatives and stimulant laxatives and examples of these different types of laxatives are shown for you.
Slide 46: We review the efficacy of bulk laxatives, there have been a number of randomized control trials looking at psyllium, which is probably the most widely used form of bulk laxative. Three of these were placebo controlled, only one of them however was well designed in terms of its methodology. And, you can see from the evidence that several of these trials show that there was a greater stool frequency with psyllium as well as better stool consistency compared to placebo. One trial showed no improvement with psyllium in terms of constipation symptoms.
The ACG gave psyllium a grade B recommendation, they gave bran no recommendation, they said that there was insufficient data to make a recommendation with regards to bran. And, there is somewhat conflicting data in poorly designed studies looking at bran.
Slide 47: What about lactulose? This is one of the osmotic laxatives and this agent actually is FDA approved for the therapy of constipation, although it’s generally used for short-term constipation.
Many of us will use this agent in an off label fashion for patients with more chronic symptoms. There have been three randomized controlled trials of this agent, all of them showed favorable effects in terms of stool frequency as well as consistency and the ACG gave this a grade A recommendation with regards to the level of evidence to support its use.
Now, there is some concern with regards to the osmotic agents and specifically lactulose. It’s most common adverse events include nausea, vomiting, diarrhea and intestinal cramps. You need to be a little bit cognizant of using this medication with regards to patients who are using high doses of antacids, not PPI’s or H2’s, but actual antacids because that could actually inhibit its efficacy. And, it is pregnancy category B has been looked at specifically in a pregnant population.
Slide 48: PEG 3350 is probably a more commonly used osmotic agent, this is recent data that was published by Jack Dipalma looking at PEG 3350 in a chronic use, up to six months of therapy. You can see on the left in terms of total patients as well as on the right two groups of elderly patients who were randomized to PEG versus placebo clearly statistically significant differences between the patients who are randomized to PEG in terms of response rate and efficacy and improvement in constipation symptoms compared to those patients who were randomized to placebo.
So, this agent does work, again it’s FDA approved for constipation and really has a indication for two weeks or less in its prescription form; over the counter form only one week or less but many of us will use this in an off label fashion for patients with more chronic symptoms and there now are some data to support that.
Slide 49: This is a summary slide looking at different types of laxatives and just the summary effective, various types of laxatives, you can see that the docusate group really has not been shown to have any significant effect on constipation symptoms whereas the bulking agents as well as stimulant laxatives do tend to have an increase in frequency effect with regard to chronic constipation symptoms.
Slide 50: What about the adverse effects of laxatives? Well, bulking agents have been associated with bloating, that’s their primary side effect, and there are other rare side effects such as anaphylactic reactions or GI luminal obstruction.
Osmotic laxatives can cause electrolyte abnormalities or even hypovolemia. And, as we mentioned with lactulose can cause some flatulence and abdominal cramping. Stimulant laxatives also can cause some abdominal discomfort as well as electrolyte imbalances. There’s not really any significant data looking at adverse events of stool softeners. But, there have been some case reports of patients in a long-term care facilities who have actually aspirated liquid forms of stool softeners, and have gotten severe numinitis. So, we do need to be cognizant of that potential as well.
Slide 51: So, we’re really left with a picture from John Johanson which is patient dissatisfaction with OTC agents, prescription agents as well as fiber. And, you can see that about 50 percent of patients are dissatisfied with regards to relief of constipation. About two-thirds say that the multiple symptoms of constipation are not improved. Three-quarters are unhappy with the lack of predictability and a similar number in terms of the lack of improvement and bloating symptoms.
Slide 52: So, we have a number of different newer agents that have become available over the last several years. Tegaserod is a serotonin agonist that has two indications: Chronic constipation in adults less than age 65, as well as irritable bowel syndrome with constipation in a female population. Now it’s important to realize that as of March 30th of this year, tegaserod has been suspended in terms of sales and marketing and its future right now is somewhat unclear as to whether it will be available again.
Recently, however, on July 27 of this year, the FDA announced that it is permitting the restricted use of tegaserod under a treatment investigational new drug protocol to treat patients with irritable bowel syndrome, with constipation, and chronic idiopathic constipation. These patients need to be women who are less than age 55, who meet specific guidelines per the FDA.
Lubiprostone is a chloride channel activator that is indicated for chronic constipation in adults, without an age limit or gender restrictions. And finally, biofeedback therapy is the treatment of choice for patients with pelvic floor dysfunction.
Slide 53: Let’s look at some of the Tegaserod data because even though it has been suspended, I think it’s worth looking at because it serves the construct for other serotonergic agents. There have been a number of phase three trials of Tegaserod in patients with chronic constipation, one was North American, one was European looking at two different doses as well as placebo.
The standard dose was six milligrams twice a day and you can see that both doses actually compared to placebo were statistically significantly superior in terms of recruiting responders, and responders as you can see in that definition had to have an increase by one complete spontaneous bowel movement per week and have completed more than seven days of therapy.
Slide 54: This was an effective therapy for some patients with chronic constipation as well as women with irritable bowel syndrome. The reason this agent was approved for patients less than age 65 was the review of clinical data and older patients did not show a statistically significant benefit relative to placebo. The reason this agent was removed from the market or suspended from the market is that in review of 29 randomized controlled trial safety data, there did appear to be a signal for an increase in cardiovascular events in patients treated with Tegaserod relative to those treated with placebo.
The incidents ratios here were zero point one percent with Tegaserod compared to zero point zero one percent with placebo, that translates into a number needed to harm of a thousand. You can see what the side effects were, where the cardiovascular events were, all of these patients it should be noted had preexisting cardiovascular risk factors. There’s no clear dose response relationship that’s been identified and there’s no relationship that’s actually been identified between the cardiovascular events as well as the treatment duration.
So, it’s still unclear whether or not this is a true association or just an unfortunate circumstance in terms of chance.
Slide 55: Now let’s talk a bit more about Lubiprostone. Lubiprostone’s the newest agent that’s been made available for chronic constipation, it is FDA approved for that indication. It’s a non-systemic agent, it acts locally to activate CLC-2 chloride channels, and what this agent does is it opens up these channels primarily in the small valve, but also to some degree in the colon and enhances chloride egress into the gut lumen with chloride flows sodium to maintain electrical neutrality and then water then flows passably through the tight junctions to maintain osmotic neutrality.
So you get an isosmotic efflux of fluid into the gut lumen, that in turn potentially causes some distention, but also solublizes the stool to some degree and helps facilitate defecation.
Now I mentioned it was non-systemic, concentrations of Lubiprostone in the plasma are below the level of quantification but some of the metabolites can be measured in very small degrees, specifically the M3 metabolite. Lubiprostone is actually a derivative of prostaglandin but has not been shown definitively to bind to prostaglandin receptors or cause smooth muscle contraction.
Slide 56: Now let’s look at some of the clinical trial data of Lubiprostone, this is data from John Johanson in which patients were randomized to Lubiprostone as a standard dose of 24 micrograms twice a day or placebo for four weeks.
And, you can see the patient started out between one and two bowel movements per week and very quickly those patients who were randomized to Lubiprostone increased their frequency up to about one bowel movement per day between six and seven bowel movements per week and that was statistically significantly improved compared to patients who were randomized to placebo.
Slide 57: There are longer term data that’s available with regards to Lubiprostone as well, there are data from a number of different safety studies that followed patients up to 48 weeks. These were open label studies that also measured to some degree some efficacy variables. And over these periods of time, patients felt that their constipation severity was overall improved, their abdominal bloating was improved as was their abdominal discomfort. Long-term use of Lubiprostone did not show any evidence of tachyphylaxis.
Slide 58: In terms of the adverse events that have been seen with this agent in the clinical trials, the most common adverse event was nausea in these trials that seems to occur as frequently as 30 percent and this is any nausea. Most of the nausea was very mild to moderate and most patients who experience nausea did not actually discontinue use of Lubiprostone.
We can have our patients minimize their incidents of nausea by advising them to take this medication with a full meal as well as an extra glass of fluid, specifically water, but any fluid really will do. Headache, abdominal pain and diarrhea also were slightly more common than placebo.
Slide 59: There is no evidence of cardiac repolarization, abnormalities or effect of Lubiprostone, no clinically significant changes in serum electrolyte levels from those open label safety studies up to a year. And, there’s a very low likelihood of drug-drug interactions because again this agent is largely non-absorbed.
Slide 60: Now I mentioned biofeedback as a newer therapy as well, and that is the primary therapy of choice for patients with pelvic floor dysfunction that we diagnosed via anorectal manometry. These are data from Chiarioni in which they took patients with slow transit constipation as well as patients with pelvic floor dysfunction or perhaps patients with a mixed pattern somewhere in between. And, they treated them with five weekly biofeedback sessions.
You can see quite clearly that the patients who had clear pelvic floor dysfunction tended to get quite a bit better compared to those patients who had slow transit constipation. And, that’s why making that distinction with regards to the type of constipation the patients have can be so important.
If we look over at the graph on the right and we see that follow-up, up to 24 months later these patients still are doing quite well after they’ve received biofeedback therapy. So, remember that therapy for patients who perhaps are not responding to a number of different classes of laxative therapies.
Slide 61: There are a number of different points at which we might consider sending a patient to a surgeon. This is typically considered a last ditch effort but for those patients who have refractory constipation in terms of multiple laxative therapies that we’ve investigated for pelvic floor dysfunction and colonic transit or perhaps those patients who have had multiple complications or important complications from their chronic constipation, those patients may benefit by surgical referral.
Slide 62 : Data with regards to surgery for constipation are somewhat scant, but shown is some recent data that’s looked at the outcomes of patients who have had surgery for chronic constipation symptoms.
And there have been multiple side effects and adverse events that have occurred in these patients, but most importantly when these patients were queried as to whether or not they thought this form of therapy helped them, 77 percent stated that they were happy that they had the surgery and they felt that it improved their quality of life.
Another study that was recently presented at digestive disease week found similar findings that patients who had colectomy felt that their quality of life was improved. That is going to be a relatively infrequent occurrence. So in terms of investigational therapies for irritable bowel syndrome with constipational loss of Tegaserod has really caused a significant rethinking of how we treat these patients.
Slide 63: Lubiprostone is FDA approved for chronic constipation, not for irritable bowel syndrome constipation but there are some data looking at Lubiprostone. Linaclotide is a guanylate cyclase-C agent and Renzapride is a combination serotonergic agent.
We’ll look a little bit more in depth at all of these agents very briefly.
Slide 64 : Lubiprostone was recently reported to improve symptoms of irritable bowel syndrome with constipation at a dose of eight micrograms BID compared to placebo. About an eight percent difference between active therapy and placebo therapy translated to a number needed to treat of about 12, which is very similar to many other agents that we’ve seen in the past that were approved for irritable bowel syndrome.
Slide 65: Linaclotide was studied in a dose ranging format and found to accelerate ascending colon emptying and also cause a significant loosening of the stool in patients with irritable bowel syndrome and constipation. So perhaps this may be an effective therapy and more data is anxiously awaited with regards to Linaclotide.
Slide 66: And finally, Renzapride, this combination serotonergic agent has been shown to accelerate colonic transit as well as ascending colon emptying. But, in the study that was published by Cammalleri in 2004, did not appear to have an overall impact on the symptoms of irritable bowel syndrome. Phase two and phase three trials are currently under way with this agent.
Slide 67: I presented an algorithm that I would suggest you might want to try with regards to the patients who come in with chronic constipation symptoms, I identify the predominant symptom and I look for red flags or secondary causes.
If these are not seen or exhibited by patients, then I think we’re in good stead to go ahead and treat these patients empirically. I would start simple with lifestyle measures as well as bulking agents or fiber, osmotic and stimulant laxatives and lubiprostone. If patients improve in terms of their symptoms, then we simply continue therapy.
We may want to contract with patients to treat them for a certain period of time, withdraw that therapy, if they have a recurrence we simply reinstitute that therapy. If they don’t respond, or if they respond partially, then we may want to layer the different types of laxative therapies on board or we may want to switch completely and move to a different class of laxative. Eventually if patients fail two or three different classes of laxatives, then I will do more directed diagnostic testing looking for colonic inertia or pelvic floor dysfunction. Certainly if patients exhibit red flags from the outset, I will do directed testing looking for organic disease or other non-GI diseases.
Slide 68: So the key points that I hope I’ve tried to convey here today include that lifestyle and diet modifications which are often recommended really don’t have a lot of evidence to support their use or their effectiveness in terms of primary therapies for chronic constipation. Stool softeners and OTC laxatives have been inadequately studied, they may very well be effective for non-consulters but the studies don’t support their use in a tertiary or refractory setting.
The current options that have been shown to be efficacious and well done randomized control trials include psyllium, lactulose, PEG 3350, which is now available OTC as well as prescription, Lubiprostone and biofeedback therapy for those patients with pelvic floor dysfunction. Now, the only group of therapies that have been shown to help patients conclusively with chronic constipation include Lubiprostone and biofeedback therapy. Remember, we have to individualize and balance the cost and adverse events and benefits for all of our patients.
We will now turn back to Dr. Kuritzky for a discussion of the case study presented at the beginning of this activity.
Slide 69: Dr. Kuritzky: Thank you, Dr. Cash.
Let’s conclude with our case now.
The clinician is addressing Martha to inform her of some good news.
“Martha, I’m glad we spoke about this, because there are several good treatment options that I think you’ll be satisfied with.”
“Well, that is good news, doctor,” says Martha.
Slide 70: As we address the important components of seeking relief in constipation, we want to identify any potential underlying causes of chronic constipation. Most cases of constipation seen in the clinician’s office are indeed functional, or primary.
But diabetes, the utilization of non-steroidal anti-inflammatory drugs or narcotics can all contribute, either alone or in concert, to induce or worsen constipation.
Slide 71: The treatment options are several. One could remove medications that are associated with constipation. At this point in Martha’s medication career, we know that she does occasionally need opioids, so we probably can’t change that.
We know that she is successfully treating blood pressure, and the medication is unlikely to be contributing, because it’s a long-term measure.
We also know that we would like her to increase her general activity and alter her diet, but she’s already taken steps in that direction.
Which leaves us with the tool that most patients usually prefer, and that is the medicinal options. Appropriate choices include things like over-the-counter laxatives, such as stimulant laxatives, or osmotics, or one of the prescription agents.
