Patient Case
CF is a 47-year-old female who presents for a second-opinion evaluation of chronic constipation and abdominal pain (Table 1). Her past medical history is significant for generalized anxiety disorder, migraines, temporomandibular joint (TMJ) disorder, depression, and gastroesophageal reflux disease (GERD). She reports a history of hemorrhoids that cause intermittent bleeding.
CF reports experiencing constipation since childhood and remembers having to use mineral oil when younger. Over the years, her symptoms changed such that she experienced several years of diarrhea with abdominal pain. However, her symptoms have returned to consistent constipation, and she estimates having bowel movements every 3 or more days. After seeing a Bristol Stool Form Scale (BSFS), she identifies that most of her stools are types 1 and 2.
In addition to constipation, CF experiences lower abdominal pain concentrated on her left side associated with bowel movements. This pain sometimes improves with defecation. She also has frequent straining during a bowel movement and often requires sitting on the toilet for 10 minutes or longer. Other symptoms that she affirms include a sense of incomplete evacuation and a sense of anorectal blockage. CF notes significant bloating with abdominal distension that typically (although not always) improves with bowel movements.
Over the years, she has relied on frequent use of polyethylene glycol. CF states that she has achieved improved bowel movement frequency (every 1 to 2 days) and consistency (BSFS types 3 and 4) with polyethylene glycol, but that her abdominal pain persists. She has also cycled through docusate (which she found to be ineffective) and senna (which led to abdominal cramping). A few years ago, her primary care physician offered a prescription of linaclotide, to which she experienced no effect until the dose was increased to 290 µg, which led to cathartic diarrhea.
CF has tried a low–fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet on her own, but found it to be too restrictive for her lifestyle; probiotics offered her no perceived benefit and she considered them very expensive. She has also supplemented her diet with fiber and kiwifruit, with little effect.
Her prior workup includes several tests. A small intestinal bacterial overgrowth (SIBO) breath test was positive; thus, she was prescribed rifaximin but experienced no symptom improvement. Laboratory testing included celiac serology and Helicobacter pylori stool antigen, both of which were negative. Thyroid-stimulating hormone levels were normal, as was complete blood count and comprehensive metabolic panel. A colonoscopy, ordered with first presentation of symptoms, was normal. Other imaging tests were then conducted, including abdominal ultrasound and computed tomography of the abdomen and pelvis. All imaging was normal.
CF’s mental health history is notable for anxiety and depression. After trialing several agents, she is currently treated with a selective serotonin reuptake inhibitor and buspirone. She states that both conditions are well controlled with treatment.
Anorectal manometry and rectal examination are performed. External hemorrhoids are visibly noted. CF exhibits decreased perineal descent while bearing down, and normal resting anal pressure with normal anal squeeze pressure. Some dyssynergia is noted with stimulated defecation. There is decreased rectal pressure upon the Valsalva maneuver. However, she is not a candidate for pelvic floor biofeedback therapy with a normal balloon expulsion time.
CF is diagnosed with irritable bowel syndrome with constipation (IBS-C). After a discussion about her treatment expectations and goals of treatment, she initiates treatment with tenapanor 50 mg twice a day. She reports significant improvement in both constipation and abdominal symptoms and her overall quality of life (QoL) at a 6-week follow-up appointment.
In the Clinic . . .
This patient was seen by other providers before she was seen in my clinic. She had undergone unnecessary testing but was never offered a comprehensive explanation of IBS-C. When one kind of therapy did not work completely, she was not offered any other option. Providers often have the approach of, “You have IBS. There’s nothing wrong with you. Try some Miralax.” And if that does not work, there is no plan B. We need a complete reset in how we approach both diagnosing and managing IBS-C, taking into account how this debilitating chronic condition impacts the QoL of our patients.
Use a Positive Diagnostic Approach
According to the Rome Diagnostic Criteria for Irritable Bowel Syndrome, fourth iteration (Rome IV criteria), IBS is associated with symptoms of recurrent abdominal pain occurring on average at least 1 day per week and associated with 2 or more of the following: related to defecation; associated with a change in the frequency of stool; or associated with a change in the form (appearance) of stool.1 Additionally, these symptoms must have been present for the previous 3 months, with onset at least 6 months prior, to confirm a diagnosis of IBS.
The Rome IV criteria were designed for defining patient enrollment in clinical trials. The Rome Foundation has proposed a modification of these criteria for use in clinical practice, whereby an IBS diagnosis can be reached if (1) the nature of the symptoms corresponds to those in the Rome IV diagnostic criteria, and (2) the symptoms are bothersome (interfering with daily activities or requiring attention, causing worry or interference with QoL).2
If this is the case, a lower frequency and a shorter duration (8 weeks or more) of symptoms than those required for the Rome IV criteria are allowed, provided that there is clinical confidence that other diagnoses have been sufficiently ruled out based on presentation and additional investigations as needed. An evaluation of the proposed modified criteria found that, when used to diagnose IBS, they were more sensitive but less specific, leading to a much lower positive likelihood ratio than the original Rome IV criteria.3
Four IBS subtypes are recognized by the Rome IV criteria: IBS-C, IBS with diarrhea (IBS-D), IBS with mixed or alternating bowel habits (IBS-M), and IBS without a significant pattern of abnormal stool (IBS-U).4 The classification of IBS subtype is made using the BSFS.5 A diagnosis of IBS-C is made with BSFS types 1 and 2 (present in more than 25% of bowel movements) together with the presence of BSFS types 6 and 7 (fewer than 25% of bowel movements). The converse is used to classify IBS-D, with at least 25% of bowel movements of BSFS types 6 or 7 coupled with fewer than 25% of BSFS types 1 or 2. IBS-M is defined by at least 25% of bowel movements of BSFS types 1 or 2, and at least 25% of bowel movements of BSFS types 6 or 7, whereas IBS-U is used to identify patients who meet the Rome IV criteria for IBS but do not fall into one of the other 3 IBS subgroups.
Notably, although abdominal pain and hard stools are the hallmark symptoms of IBS-C, many patients report other significant abdominal symptoms (including discomfort and bloating), as well as other bowel-related symptoms (such as infrequent stools, straining, and the feeling of incomplete evacuation). However, of these, only abdominal pain is reflected in the Rome IV criteria.
Guidelines from the American College of Gastroenterology include recommendations regarding a positive diagnostic strategy based on Rome IV criteria.4 This positive diagnosis of IBS involves a comprehensive clinical assessment that considers medical history and physical examination (Figure 1).6 Findings from this assessment are compared with the Rome IV criteria. The clinical assessment should include evaluation for a set of alarm features that, if present, should trigger immediate investigation and treatment, as they are indicative of another gastrointestinal (GI) disorder.7,8 These alarm features include new symptoms in a patient older than 50 years, unintended weight loss (>10% in 3 months), hematochezia not caused by hemorrhoids or anal fissures, symptoms that awaken the patient at night, fever, anemia, acute or rapidly progressing symptoms, a palpable mass, ascites, or lymphadenopathy, or a family history of colorectal cancer, polyposis syndrome, celiac disease, or inflammatory bowel disease (IBD).
Abdominal pain and constipation symptoms are enough to meet the Rome IV criteria in most patients, supporting a positive diagnosis without the need for further testing. However, certain testing strategies may aid in the diagnosis in appropriate patients for whom other conditions must be excluded.4 For example, serology testing may aid in the exclusion of celiac disease for patients with diarrhea symptoms, and fecal calprotectin can be part of a normal workup in IBS-D (as well as colonoscopy in patients for whom there is suspicion for microscopic colitis). Neither is recommended for IBS-C, however.
In the Clinic . . .
There is no workup or biomarker test that can be used to diagnose IBS-C. In this patient, testing for both celiac serology and H. pylori stool antigen were negative, the colonoscopy was normal, and cross-sectional imaging and a thyroid study test were negative. Although the SIBO breath test was positive, there is controversy regarding the importance of this for selecting IBS treatments. Notably, none of these tests was necessary to make a definitive IBS-C diagnosis and indeed they delayed the eventual diagnosis. Instead, her long-term symptoms of recurrent abdominal pain related to bowel movements and sometimes improving with defecation were more than sufficient to make a positive diagnosis of IBS-C.
Delay in IBS-C Diagnosis
IBS usually starts at a young age, with about one-half of patients reporting that they first experienced symptoms before they were 35 years old.9 However, most patients never present for care, and those who do so generally present much later. In my experience, it takes about 4 years after onset for a confident IBS-C diagnosis, an observation supported in the literature.10,11 There are a multitude of factors responsible for this long diagnostic journey in IBS-C.
Often providers take a rule-out approach to the diagnosis of IBS-C as opposed to a rule-in one. This occurs despite well-established guidelines that point to the importance of making a positive diagnosis.4 As a result, the diagnosis of IBS-C can be missed or delayed despite (or in some cases, because of) testing.12 A survey of 472 gastroenterologists, internists, and family physicians found that the majority of gastroenterologists commonly order laboratory tests, with almost one-third performing flexible sigmoidoscopies or colonoscopies in response to reported IBS symptoms.13 Another study found that physicians who consider IBS a diagnosis of exclusion ordered an average of 1.6 more diagnostic tests than physicians who use a positive IBS diagnostic strategy.14
Another important reason for delayed diagnosis is the stigma associated with IBS-C.15,16 Providers often worry about disappointing a patient with a diagnosis of IBS-C and are unsure about the existence and/or efficacy of available treatment options. In practice, this often translates to giving patients the message of “It’s just IBS. There’s not much that we can do for you.” Friends often advise to “just stress less and relax and you will be fine.” Then patients often internalize this stigma and, because it is a condition that gets worse under stress, they believe that “this isn’t something that I should be bothering my physician or my family with” even though it has a monumental impact on their QoL.
One other factor that is responsible for delayed diagnosis is that the symptoms wax and wane over time. Hence patients often do not present to the gastroenterologist until they have reached their breaking point, with symptoms causing a debilitating impact on their QoL.
In the Clinic . . .
Realize that your patient has likely suffered a long time prior to being seen in your clinic.
Educate the Patient: What Is IBS-C?
Education is a critical component of the management of a patient with IBS-C. Patients should be informed that IBS is a functional bowel disorder (Figure 2)7 now referred to as a disorder of gut-brain interaction.17-19 The gut may be sending abnormal signals of pain and discomfort to the brain, and/or the brain may be sending abnormal signals back to the gut that can lead to worsening symptoms.
The pathophysiology of IBS-C is considered to be multifactorial.20-25 Changes in gut motility and water imbalances are thought to account for the development of hard stools and decreased defecation.22,23 Aberrant interactions between the gut microbiome and the immune system may explain alterations observed in gut permeability (arising from loss of intercellular tight junctions and reduced transepithelial electrical resistance). These dysregulated interactions may also account for the induction of inflammatory responses localized to nerve fibers throughout the gut epithelium and resulting in changes to microbiome-immune interactions.24,25 Changes in the gut microbiome can exacerbate gut inflammation and immune activation.24,25 Finally, visceral hypersensitivity can explain the enhanced sensitization of afferent nerve pathways within the intestines.24,26
Patients frequently switch IBS subtypes over time.27,28 A prospective assessment of 317 female patients with IBS found that, within 1 year, 75% of patients changed subtypes, and 29% switched between constipation-predominant IBS and diarrhea-predominant IBS.29 It can be helpful and reassuring for patients to learn that switching between IBS-D to IBS-C over time is not uncommon.
In the Clinic . . .
Establish a patient–provider relationship, which has been shown to be an independent predictor of the likelihood of success in IBS-C management. Explaining the nature of IBS-C can itself be therapeutic as well as aid in making a positive diagnosis.
Realize that Abdominal Symptoms Are as Debilitating as Constipation
As a result of the complex and multifactorial pathophysiology underlying IBS-C, patients with IBS-C experience a range of symptoms beyond constipation. Indeed, abdominal pain and hard stools, considered the hallmark symptoms of IBS-C, may be accompanied by other abdominal symptoms (discomfort, bloating) and bowel-related symptoms (infrequent stools, straining, sensations of incomplete evacuation). Although these symptoms are not specifically included in the Rome IV criteria, they are recognized as important by patients and providers. However, few of these have been included in any primary study endpoints in the pivotal clinical trials of the agents approved for IBS-C; they are included in many of the secondary endpoints of these trials.
The IBS in America 2024 survey showed that, in addition to constipation (reported by 94% of respondents), many other symptoms were experienced by individuals with IBS-C.30,31 Among the most frequent of these were bloating (86%), abdominal cramps and pain (85%), abdominal fullness (73%), excessive gas or flatulence (68%), fatigue (64%), tenesmus (57%), and heartburn or GERD (51%). Of the 95% of patients who experienced abdominal pain within the past 7 days, 33% described the pain as quite bad or very bad and interfered with their day-to-day activities quite a bit (20%) or very much (9%).
Overall, these symptoms ultimately mean that patients with IBS-C experience significantly worse QoL compared with individuals without IBS-C. Several studies have demonstrated that IBS-C symptoms have a negative effect on measures of health-related QoL.32-35 This was also demonstrated in the IBS in America 2024 survey, as the overwhelming majority of respondents (90%) reported at least some negative (68%) or significant negative (22%) impact of IBS-C on their overall QoL.36 Mental/emotional health was also negatively affected, with 54% of respondents reporting at least some negative impact and 25% reporting significant negative impact. Other negative impacts on QoL apparent among survey respondents included sexual health and intimacy (40% some negative; 24% significant negative), employment and/or education (31% some negative; 17% significant negative), sense of independence (43% some negative; 16% significant negative), relationships with friends or family (42% some negative; 14% significant negative), and household finances (31% some negative; 12% significant negative).
In the Clinic . . .
Instead of emphasizing to patients that IBS-C is not something that will impact their mortality, acknowledge that this can be a very debilitating condition, and explore specific treatment options that have been proven to impact all symptoms of IBS-C, not just constipation.
Understand the Existence of Common Comorbid Disorders
There is a high degree of association of IBS with psychiatric and psychological conditions, in particular with anxiety and depression.37 There is an estimated threefold-higher risk of anxiety and depression in individuals with IBS compared with healthy controls.38 These conditions may present as diagnosed psychiatric disorders or as subclinical symptoms in the patient.39 A meta-analysis reported that co-occurring anxiety and depressive disorders were prevalent in 23% of individuals with IBS. This same analysis showed that the prevalence of symptoms of anxiety and depression among patients with IBS was 39% and 29%, respectively.40
Several studies suggest a causal link between psychological conditions and GI symptoms, at least in subgroups of people with IBS. A systematic review of 11 studies found that individuals with depression had a twofold-higher risk of comorbid IBS and a nearly twofold-higher risk of developing new-onset IBS than individuals without depression.40 The mechanisms underlying the connection between IBS and mental health are unclear but have been attributed to dysregulation of the hypothalamic-pituitary-adrenal axis, immune activation, or genetic mechanisms.41 A genome-wide analysis of 53,400 people with IBS identified 6 genetic susceptibility loci for IBS, of which 4 are also associated with mood and anxiety disorders, expressed in the nervous system, or both.42 This analysis also showed a robust genome-wide association between the risk of IBS and anxiety, neuroticism, and depression. These findings were considered a result of shared pathogenic pathways and not attributed to anxiety-causing abdominal symptoms.
Comorbid chronic pain conditions are prevalent in patients with IBS, most commonly fibromyalgia, chronic fatigue syndrome, and chronic pelvic pain.43 In a large analysis of a hospitalization database, the prevalence of fibromyalgia (adjusted odds ratio [OR], 5.33; 95% CI, 5.24-5.41; P<.001) and chronic fatigue syndrome (adjusted OR, 5.40; 95% CI, 5.04-5.78; P<.001) were both significantly higher in patients with IBS vs the general adult population without IBS.44 A survey of 5650 US adults (of whom 186 met criteria for IBS) reported that IBS was associated with increased odds of headache (adjusted OR, 2.18; 95% CI, 1.41-3.38) and chronic back or neck pain (adjusted OR, 2.74; 95% CI, 1.88-4.00).45 Note that TMJ disorder, as was experienced by the patient in this case, may also be linked to IBS.46,47
IBS-C and defecation disorders can coexist in the same patient; often both need to be addressed. Dyssynergic defecation is a condition in which the pelvic floor and abdominal muscles that are involved in bowel movements do not coordinate properly, leading to difficulty in passing stool. Symptoms of dyssynergic defecation include painful defecation, straining, incomplete evacuation, and a sensation of blocked evacuation.48 Multiple studies have shown that the positive and negative predictive value of symptoms alone is inadequate for the diagnosis of dyssynergic defecation. Other anorectal symptoms (constipation, fecal incontinence, and anorectal pain) may be present,49 but they do not correlate with anorectal physiology on testing.
In the Clinic . . .
Be prepared that patients with IBS-C may present with comorbid conditions.
Recognize that Polyethylene Glycol, Fiber, and Probiotics Have a Limited Role in IBS-C
Many drugs that are not specifically approved for IBS-C can have an impact on bowel movements; however, not only do they not address the abdominal pain component of IBS-C, they may worsen these symptoms.
Laxatives are commonly employed in patients with IBS-C (either self-prompted or under clinical advice).50 However, although both osmotic and stimulant laxatives can improve constipation symptoms, they have little effect on abdominal pain.51 Further, stimulants can worsen abdominal cramps, discomfort, and pain.52 The osmotic agent polyethylene glycol can improve the consistency and frequency of bowel movements. However, it does not alleviate pain, leaving patients with unaddressed IBS-C symptoms. Guidelines offer conflicting views on the use of polyethylene glycol in IBS-C.4,53
Fiber has been investigated as an intervention in IBS-C.54,55 Commercially available soluble fibers such as psyllium are recommended, whereas insoluble fibers such as bran may worsen symptoms and are generally not recommended in patients with IBS-C. Psyllium has the best evidence for use in IBS and constipation, resulting in increases in stool bulk and normalization of colonic transit.56 Psyllium is slowly fermented and may cause a low degree of bloating. Methylcellulose can be useful in constipation, causing an increase in colonic transit, and is nonfermentable and therefore not associated with bloating.
Probiotics have been shown to improve overall stool frequency, gut transit time, and stool consistency in patients with IBS.57 Bacillus coagulans strain LBSC (DSM 17654) was demonstrated to improve IBS symptoms such as bloating, abdominal pain, constipation, and diarrhea, and also resulted in improved QoL.58 However, higher-quality studies have generally demonstrated a very limited effect of probiotics on IBS symptoms, and the American Gastroenterological Association (AGA) guidelines include no role for probiotics in the management of IBS-C.53
In the Clinic . . .
Polyethylene glycol, fiber, and probiotics have a limited role in managing IBS-C. Even if they address constipation, they may worsen abdominal symptoms. Using these without addressing abdominal symptoms may increase your patient’s frustration with treatment.
Use FDA-Approved Treatment Options for IBS-C
There are now 4 currently available agents approved by the US Food and Drug Administration (FDA) with specific indication for IBS-C: lubiprostone, linaclotide, plecanatide, and tenapanor.59-62 Of these, lubiprostone is only approved for women 18 years or older with IBS-C. Both lubiprostone and linaclotide have multiple dosing options. FDA-approved dosing options for these agents are 8 µg twice daily for lubiprostone, 290 µg once daily for linaclotide, 3 mg once daily for plecanatide, and 50 mg twice daily for tenapanor.
These agents are classified according to their varying mechanisms of action (MOAs) (Figure 3).63 Three of these 4 agents are classified as secretagogues (lubiprostone, linaclotide, and plecanatide) and one as a retainagogue (tenapanor).
Lubiprostone is a prostaglandin E1 derivative that activates the intestinal type 2 chloride channel (CIC-2).64 Located on the apical surface of small intestinal enterocytes, CIC-2 results in chloride efflux into the luminal cavity. This in turn causes fluid secretion into the luminal cavity, leading to stool softening and acceleration of intestinal transit. Two other secretagogues, linaclotide and plecanatide, are peptides that act as agonists to the guanylate cyclase-C (GC-C) receptor.65-67 Activation of the GC-C receptor, located on the luminal surface of intestinal enterocytes, triggers intestinal secretion that causes stool softening and intestinal transit acceleration.
The fourth FDA-approved agent, tenapanor, is a locally acting inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3), expressed on the apical surface of the epithelial cells lining the small intestine and colon that is primarily responsible for the absorption of dietary sodium.68-71 Tenapanor is thought to act via 3 mechanisms.71 The first of these is by decreasing the absorption of dietary sodium, which causes luminal water content to be retained, intestinal transit time to be accelerated, and stool to be softened; because of these actions, tenapanor is referred to as a retainagogue. Animal models have suggested a second mechanism in which tenapanor narrows the tight junctions between intestinal epithelial cells, resulting in decreased intestinal permeability. The third mechanism, also demonstrated in animal models, involves a reduction of visceral hypersensitivity.
All 4 agents discussed were approved by the FDA based on results from pivotal, large, randomized and placebo-controlled trials (summarized in Table 2).63 Lubiprostone was compared with placebo in a combined analysis of two 12-week phase 3 trials.72 A patient was considered an overall responder (primary endpoint) if they were a monthly responder for at least 2 of the 3 months of the study. In this combined analysis, there were a significantly higher percentage of overall responders in the lubiprostone group vs the placebo group (17.9% vs 10.1%; P=.001). These overall responses rose over time, with the percentage of patients achieving the primary endpoint with lubiprostone vs placebo increasing over the first 3 months of treatment (month 1: 10.8% vs 7.5%; month 2: 18.3% vs 11.4%; month 3: 22.0% vs 14.5%). Patients who achieved an overall response also experienced significant improvements in other symptoms, including abdominal discomfort or pain, bloating, constipation severity, stool consistency, and straining (P<.001 for all symptoms reported in overall responders vs nonresponders).
Linaclotide was compared with placebo in 2 phase 3 trials.73,74 In both studies, the primary endpoint was the FDA combined endpoint for IBS-C response, defined as an improvement of at least 30% from baseline in average daily worst abdominal pain score and an increase of at least 1 complete spontaneous bowel movement (CSBM) from baseline, both in the same week for 6 or more out of 12 weeks. In the first 26-week study, significantly more patients treated with linaclotide achieved the FDA combined endpoint vs placebo (33.7% vs 13.9%; P<.0001).73 In the second 12-week study, the FDA combined endpoint was also significantly improved with linaclotide vs placebo (33.6% vs 21.0%; P<.0001).74 In both studies, linaclotide also resulted in significant improvements compared with placebo across multiple other endpoints. In the 26-week study, these included improved abdominal pain for 9 out of 12 weeks (48.9% vs 34.5%) and CSBM response for 9 out of 12 weeks (47.6% vs 22.6%). In the 12-week study, linaclotide treatment was associated with significant improvements across several other outcomes during at least 6 of the 12 treatment weeks, including reduction in abdominal pain of 30% or greater (50.1% vs 37.5%; P=.0003) and an increase of at least 1 CSBM from baseline (48.6% vs 29.6%; P<.0001).
Plecanatide was compared with placebo in 2 identically designed phase 3 clinical trials, both of which used the same FDA combined primary endpoint of overall response.75 In Study 1, plecanatide was associated with a significantly higher percentage of patients who achieved the primary endpoint vs placebo (30.2% [3 mg arm] and 29.5% [6 mg arm] vs 17.8%; P<.001). Similar results were achieved in Study 2 (21.5% [3 mg arm] and 24.0% [6 mg arm] vs 14.2%; P=.009). All secondary endpoints evaluated in both studies were significantly improved with plecanatide compared with placebo, including stool frequency/consistency, straining, and abdominal symptoms.
Several follow-up analyses of these 2 trials focusing on other symptom improvement have been reported. One of these was a reanalysis of data from these studies using a novel trisymptom composite endpoint.76 This composite endpoint consisted of abdominal pain, abdominal bloating, and CSBMs. Significantly more patients in the plecanatide group achieved this trisymptom composite response compared with the placebo group. In a separate report, plecanatide efficacy was evaluated in patients with IBS-C stratified by bloating intensity.77 Among patients classified as having moderate-to-severe bloating, plecanatide significantly reduced bloating severity compared with placebo (least-squares mean change [LSMC], –1.7 vs –1.3; P=.002), reduced abdominal pain (–1.7 vs –1.3; P=.006), and increased CSBM frequency (1.4 vs 0.8; P<.0001). A systemic review and meta-analysis of the efficacy and safety of plecanatide assessed 4 outcomes in patients with IBS-C.78,79 At the FDA-approved dose of 3 mg once daily, the pooled effect size favored plecanatide vs placebo: abdominal pain (pooled effect size, –0.49; 95% CI, –0.88 to –0.09; P=.03); change in BSFS score (pooled effect size, 0.82; 95% CI, –0.53 to 2.18; P=.12); change in CSBM (pooled effect size, 0.53; 95% CI, –1.77 to 2.83; P=.42); and change in straining score outcome (pooled effect size, 0.39; 95% CI, –1.21 to 1.99; P=.40).
Tenapanor was evaluated in 2 placebo-controlled, randomized, phase 3 studies: T3MPO-1 (a 12-week trial) and T3MPO-2 (a 26-week trial).80,81 The primary endpoint of the FDA combined endpoint for IBS-C was significantly improved in both trials. In T3MPO-1, significantly more patients in the tenapanor arm compared with the placebo arm met the primary endpoint (27.0% vs 18.7%; Cochran-Mantel-Haenszel [CMH] P=.020).80 The T3MPO-2 trial reported similar outcomes in the primary endpoint (36.5% vs 23.7%; CMH P<.001).81
In T3MPO-1, the abdominal pain response was improved with tenapanor (44.0% vs 33.1%; CMH P=.008), although the rates of CSBM response were similar between the tenapanor and placebo groups (33.9% vs 29.4%; CMH P=.270).80 Tenapanor also led to significant improvements across several measures of abdominal symptoms for at least 9 of 12 weeks compared with placebo, including abdominal discomfort response (29.0% vs 17.1%; CMH P<.001), rate of abdominal bloating response (27.0% vs 16.1%; CMH P=.001), abdominal cramping response (30.6% vs 23.1%; CMH P=.044), and abdominal fullness response (27.4% vs 14.4%; CMH P<.001).
In T3MPO-2, both the abdominal pain response (49.8% vs 38.3%; CMH P=.004) and improvement in CSBM (47.4% vs 33.3%; CMH P<.001) endpoints were significantly improved with tenapanor compared with placebo.81 Patients experienced an improvement in abdominal pain with tenapanor as early as 1 week after beginning treatment. Tenapanor was also associated with a decrease in other abdominal symptoms including bloating, fullness, discomfort, and cramping.
A post hoc analysis of pooled data from the T3MPO-1 and T3MPO-2 trials examined the efficacy of tenapanor on abdominal symptoms.82,83 An abdominal score (AS) was calculated as the average of weekly scores for abdominal pain, discomfort, and bloating symptoms. The LSMC from baseline in AS was significantly improved with tenapanor compared with placebo (–2.66 vs –2.09; P<.0001). The AS response rate was significantly higher for tenapanor for at least 6 out of 12 weeks (44.4% vs 32.4%; P<.0001) and for at least 9 out of 12 weeks (30.6% vs 20.5%; P<.0001).
Unsurprisingly, GI-related adverse events are the most frequently reported side effects across all 4 agents. These include nausea, diarrhea, and abdominal distension; are generally mild or moderate in severity; and can be effectively managed.
In the Clinic . . .
FDA-approved IBS-C medications are safe and effective, and positively impact both bowel and abdominal symptoms. They have been evaluated in pivotal, large, randomized controlled trials. Your patient has likely suffered a long time prior to being seen in your clinic. Once you make a positive IBS-C diagnosis, consider starting your patient on an FDA-approved treatment for IBS-C. Prompt initiation of effective therapy is your responsibility.
Defining Treatment Response: Setting Expectations
The first step in setting treatment expectations is understanding the goal of each patient. When I ask my patients their goal for their visit with me, the answers range from “I just want to feel better” to “I just want to know that I do not have cancer.” Therein lies the advantage of making a confident positive diagnosis of IBS-C. You can assure your patients that studies have proven no connection between IBS-C and increased risk of mortality.
The next step is defining what “feeling better” would look like for each patient. Data from the US population shows that normal bowel movement frequency is anywhere from 3 times per week to 3 times per day, with BSFS type 3 and 4 for most people.84,85 So my aim is to get my patients’ bowel frequency and consistency in that range.
Then we talk about percentage in overall improvement, which considers abdominal symptoms as well. Unlike IBD, in which a stool-based marker or colonoscopy results indicate the level of inflammation, in IBS-C we are pursuing significant QoL improvement as the goal of therapy. So, although I tell my patients that they may never have a CSBM every single day, they should definitely expect improvement in both the frequency and consistency of their bowel movements along with significant improvement in abdominal pain, straining, and bloating. My goal is to have my patients experience at least 50% or more improvement overall on their IBS-C medication.
To establish these expectations, I encourage my patients to define what “much improved” would mean for them. Often patients identify what is bothering them the most, which usually varies among patients. I ask them to identify the 1 symptom they want to get rid of: Is it pain? Is it constipation? Is it anorectal symptoms like straining and incomplete evacuation? And that is the guide for evaluating significant treatment response for each individual patient.
In the Clinic . . .
Patients with IBS-C have been stigmatized for so long, and as physicians we should acknowledge that and reassure our patients that the aim of treatment is significant QoL improvement, not just bowel frequency improvement.
Setting Expectations: “Chronic Disease Requires Chronic Treatment”
I explain to my patients that, with successful IBS-C treatment, their bowel movements will be more frequent and abdominal symptoms will improve. Overall, there will be significant improvement in their QoL, and they should expect to improve over time. However, equally important is that they realize that IBS-C is a chronic disease that requires chronic treatment. Because of this, patients must remain on daily therapy. IBS-C medication adherence may be influenced by the occurrence of comorbidities, which may predict treatment discontinuation.86 A common cause of treatment discontinuation is intolerance (primarily diarrhea), which may be effectively managed via dose adjustment87 or trial of an alternative agent. Loss of prescription drug coverage and insufficient efficacy derived from therapy are other factors that may trigger treatment discontinuation.
In the Clinic . . .
Educate your patients that IBS-C medications are not rescue medications. The goal of taking IBS-C medication is not an immediate bowel movement. They are maintenance therapies that you take to improve all symptoms of IBS-C.
Tailoring Treatment in Case of Inadequate Response: Raising Expectations
IBS-C is a heterogeneous disorder. In some patients, their IBS-C may be more related to peripheral factors such as their bowels; in others, it may be more related to central factors such as psychosocial issues. The multifactorial pathophysiology of IBS-C means that patients may respond completely differently to agents with different MOAs.21,88 There is currently no way of knowing which specific MOA will work for each patient. Therefore, if one IBS-C medication has not worked well, it does not mean that another will also fail—hence the need for an empirical approach.
The comparative efficacies between these agents are unknown in the absence of head-to-head trials. However, initiating treatment with any of these agents is clearly better than no treatment, as demonstrated in 2 meta-analyses of randomized controlled trials of these agents. The first of these found that all 4 FDA-approved agents for IBS-C were superior to placebo for the treatment of global IBS-C symptoms and demonstrated similar efficacy across most endpoints.89 The second analysis found that the FDA-approved agents for IBS-C were superior to placebo with respect to improvement in abdominal bloating.90
Although symptom improvement can often be noted within the first week of treatment, most patients require longer courses of therapy before achieving a response. Further, bowel symptoms tend to respond more rapidly than abdominal pain symptoms or bloating, so it is important to continue a medication for sufficient time to allow the patient to achieve their treatment goals.91
This was demonstrated in a post hoc analysis of pooled data from 3 studies of tenapanor (T3MPO-1, T3MPO-2, and a phase 2b study).92 In tenapanor-treated patients, the median time to CSBM response was 2 weeks, whereas the time to abdominal symptom relief was longer. The median time to abdominal pain response was 4 weeks and the median time to abdominal bloating response was 5 weeks. A post hoc analysis of linaclotide trials also suggests that, although over one-half of patients with IBS-C treated with linaclotide experienced response for abdominal pain, discomfort, and bloating or CSBM frequency within 4 weeks of treatment initiation, another 8% to 17% exhibited a response between weeks 5 and 12.93
In the Clinic . . .
I explain to my patients that we don’t have comparative data of the FDA-approved IBS-C medications. This essentially means that most likely we have to use a trial-and-error method to find the medication that works for them. Reiterate and ensure that your patient understands that this trial-and-error approach is absolutely fine and will ultimately help improve their QoL. Side effects also play a role in this decision. The reality is that many patients go through a variety of different medications before we find one that addresses all their IBS-C symptoms and improves their QoL. So, if we need to persist with treatment or change their treatment to one with a different MOA, we should do so until we find what works for each individual patient. The best medication for any given patient is the one they actually take, meaning it’s effective, well tolerated, and not too expensive.
Bringing It All Together: Treatment Algorithm for IBS-C
The AGA guidelines include a treatment algorithm for IBS-C.53 However, this algorithmic approach does have its limitations. The AGA guidelines focus on patient–provider relationship, fiber, a low-FODMAP diet, lifestyle modifications, education, reassurance, laxatives, and pain medication as first-line treatment followed by FDA-approved IBS-C medications as second-line options. Patient education is a significant step in establishing patient–provider relationship (Figure 4). However, the AGA treatment algorithm provides no guidance on switching MOAs in case of inadequate response with one medication; I believe this is an educational gap.
In the patient we are discussing, linaclotide did not work at all until the 290 μg dose when it worked “too well”. Then I switched to tenapanor, which has a unique MOA. The patient responded well, with improvement in both bowel and abdominal symptoms.
We, as physicians, need to educate our patients and ourselves, raise our expectations regarding the outcome of managing IBS-C, and try everything in our toolkit until our patients experience significant improvement in their QoL (Figure 5).
Disclosures
Dr Staller is a consultant/advisor for Anji, Ardelyx, Gemelli, Laborie, Mahana, ReStalsis, Salix, Sanofi, and Takeda; and has received research funding from Ardelyx and ReStalsis.
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