Irritable Bowel Syndrome with Constipation: Diagnosis and Multisymptom Management Beyond Abdominal Pain and Bowel Movement Frequency: A Review

Abstract

Approximately one-third of patients with irritable bowel syndrome (IBS) have IBS with constipation (IBS-C). Cardinal symptoms of IBS-C are abdominal pain and reduced bowel movement frequency. However, additional symptoms, including abdominal discomfort, bloating, and straining, are prevalent and are some of the most bothersome symptoms for patients, providing a clinical rationale for efficacy assessments that encompass simultaneous improvement in multiple IBS-C symptoms. This review highlights the diagnostic approach to IBS-C, including differentiation from chronic idiopathic constipation (CIC), and expands on data supporting multisymptom treatment beyond cardinal symptoms. Several medications are indicated for IBS-C, including secretagogues such as guanylate cyclase C agonists (plecanatide, linaclotide) and chloride channel activators (lubiprostone [women only]), as well as sodium/hydrogen exchanger 3 (NHE3) inhibitors (tenapanor). An integrated approach to treatment of IBS-C, particularly in patients with persistent symptoms after treatment with first-line secretagogues or NHE3 inhibitors, may include neuromodulators, appropriate antibiotic regimens in those with intestinal methanogen overgrowth (IMO), and/or nonpharmacologic approaches including dietary interventions and brain–gut behavioral therapies. Effective treatment plans for IBS-C should target the most bothersome symptoms, including a collaborative discussion of risks/benefits of various treatments, culminating in an agreement on a path forward between the patient and healthcare provider.

Key Summary Points

Coexisting gastrointestinal (GI) symptoms may be more distressing than the cardinal symptoms of constipation and abdominal pain in patients with irritable bowel syndrome with constipation (IBS-C).

Evaluating treatment response to coexisting IBS-C symptoms may provide more comprehensive benefit, rather than focusing solely on reduced bowel movement frequency and abdominal pain.

Pharmacologic treatments indicated for IBS-C include secretagogues (guanylate cyclase-C agonists and chloride channel activators) and sodium/hydrogen exchanger 3 (NHE3) inhibitors, and several have demonstrated efficacy in improving both cardinal and coexisting GI symptoms, using individual and novel multisymptom endpoints.

In addition to treatment with first-line secretagogues or NHE3 inhibitors indicated for IBS-C, an integrated approach to management may also include neuromodulators, antibiotic treatment for intestinal methanogen overgrowth, dietary interventions, and brain-gut behavioral therapies.

Introduction

Irritable bowel syndrome (IBS) is a gastrointestinal (GI) disorder caused by underlying disturbances in gut–brain interactions (i.e., disorder of gut–brain interaction). The estimated US prevalence is approximately 5% higher than other commonly known GI conditions, such as celiac disease (0.7%) and inflammatory bowel disease (0.5%) [1–3]. IBS is typically further classified based on predominant stool form (e.g., constipation, diarrhea) [4]. Approximately one-third of patients with IBS have IBS with constipation (IBS-C) [5, 6]. Constipation and abdominal pain are considered cardinal symptoms of IBS-C (Rome criteria) [4, 6]. However, patients commonly report additional GI symptoms, including abdominal discomfort, bloating, and straining during bowel movements (Fig. 1; [7–10]). For many patients, these additional symptoms are more distressing than cardinal IBS-C symptoms [7, 11].

Fig. 1.

Multiple GI symptoms commonly observed in patients with IBS-C. GI gastrointestinal, IBS-C irritable bowel syndrome with constipation

IBS-C symptoms can negatively impact patients’ mental health and health-related quality of life (QoL) [8]. Impaired QoL is greater among individuals with IBS-C compared with matched controls, including daily activity impairment, higher work presenteeism, and work productivity loss [8, 12]. Additionally, patients can feel frustrated, ashamed, and/or embarrassed, leading to a negative self-image and social withdrawal. Furthermore, the IBS subtype can influence daily functioning. Significantly greater negative interpersonal impacts, including self-consciousness, avoidance of sex, and difficulty concentrating, have been reported for individuals with IBS-C compared with those experiencing IBS with diarrhea (IBS-D), whereas those with IBS-D have reported significantly more reluctance to leave home and avoidance of places without easy bathroom access (P < 0.004 for all comparisons) [13].

The aim of this narrative review is to discuss the diagnostic approach to IBS-C and to highlight the multisymptom burden of IBS-C and potential treatment options, with a focus on medications with regulatory approval for treatment of the disorder. Case vignettes are included to illustrate key concepts for healthcare providers (HCPs).

Methods

The PubMed database and Google Scholar were searched for English-language articles published through April 30, 2025. Search terms included “irritable bowel syndrome with constipation” OR “constipation predominant irritable bowel syndrome” OR “IBS-C” AND “abdominal discomfort,” “abdominal pain,” “bloating,” “distention,” “multisymptom,” “nausea,” “pain,” “straining,” OR “quality of life OR QoL.” This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Diagnosis of IBS-C

Although there are symptomatic similarities between IBS-C and chronic idiopathic constipation (CIC), abdominal pain—a predominant symptom in IBS-C—is one hallmark feature that can help distinguish between these conditions (Table 1; [4, 14]). While patients with CIC may experience abdominal pain, by definition they do not experience it to the same frequency or intensity as patients with IBS-C. Abdominal pain is one of the most common reasons individuals with IBS-C seek medical care [15]. IBS-C is also associated with greater symptom and disease burden compared with CIC [16].

Table 1.

Diagnostic criteria for IBS-C and CIC (Rome IV criteria) [4]

IBS-Ca	CIC
Time frame of criteria: previous 3 months with onset ≥ 6 months before diagnosis	Time frame of criteria: previous 3 months with onset ≥ 6 months before diagnosis
• Recurrent abdominal pain, on average, ≥ 1 day per week associated with ≥ 2 of the following:	• Must include ≥ 2 of the following during > 25% of bowel movements:
Related to bowel movement	Straining
Change in frequency of stool	Lumpy/hard stoolsb
Change in stool appearance (form)	Sensation of incomplete evacuation
• Constipation: lumpy/hard stoolsb> 25% of bowel movements	Sensation of anorectal obstruction or blockage
	Manual maneuvers used to facilitate bowel movement
	• < 3 spontaneous bowel movements per week
	• Loose stools are rarely present without use of laxatives
	• Does not meet criteria for IBS

CIC chronic idiopathic constipation, IBS irritable bowel syndrome, IBS-C irritable bowel syndrome with constipation

^aIBS-C is distinct from other IBS subtypes (IBS with diarrhea, IBS mixed bowel habits, and IBS unclassified)

^bTypes 1 or 2 on Bristol Stool Form Scale

In a survey of US adults (IBS-C [n = 328]; CIC [n = 552]), patients with IBS-C experienced symptoms more days/week on average than those with CIC [16]. Significantly more patients with IBS-C versus CIC reported that symptoms—abdominal discomfort, abdominal pain, bloating, and straining—were “very or extremely bothersome” (all P < 0.04) [16]. In another survey (IBS-C [n = 275]; CIC [n = 734]), IBS-C was associated with greater prevalence and intensity of GI symptoms compared with CIC, particularly abdominal pain and bloating [9]. Further comparisons have revealed that IBS-C is also more commonly associated with comorbid psychological conditions (e.g., anxiety, depression), functional dyspepsia, and fibromyalgia, whereas CIC is more often associated with metabolic conditions (e.g., diabetes, obesity). Prosecretory agents have potential benefit in both conditions [17]. However, while over-the-counter (OTC) agents (e.g., stimulant laxatives and polyethylene glycol [PEG]) can have a role in CIC management, these products have limited to low evidence of efficacy in IBS-C [17].

The American College of Gastroenterology (ACG) guideline recommends a positive, rather than exclusionary, diagnostic strategy for patients experiencing symptoms suggestive of IBS to improve the time to initiation of appropriate therapy and cost-effectiveness (Fig. 2; [18]). In patients without alarm features (e.g., unexplained anemia or weight loss, rectal bleeding), a positive diagnostic strategy has demonstrated safety comparable to an exclusionary diagnostic strategy [19]. Current diagnostic criteria (Rome IV) for IBS specify recurrent abdominal pain symptoms ≥ 1 day/week during the previous 3 months associated with ≥ 2 of the following: (1) related to defecation; (2) change in stool frequency; or (3) change in stool form/appearance (Table 1; [4]). The IBS-C subtype is defined as > 25% of bowel movements with types 1/2 on the Bristol Stool Form Scale (i.e., constipation) and < 25% of bowel movements with stool types 6/7 (i.e., diarrhea) [4]. In clinical practice, pain symptom frequency criteria may be reduced and duration shorted to ≥ 2 months if considered bothersome to the patient [20]. An update of diagnostic criteria for IBS (Rome V) is anticipated in 2026 and will likely include abdominal pain/discomfort.

Fig. 2.

Diagnosis of IBS-C [4, 18, 20]. Note: ^aIf symptoms are bothersome, a lower frequency of occurrence and shorter (≥ 2 months) duration of symptoms may be acceptable if there is confidence that other diagnoses have been adequately ruled out based on presentation and additional investigations, as necessary. ACG American College of Gastroenterology, BSFS Bristol Stool Form Scale, GI gastrointestinal, IBS-C irritable bowel syndrome with constipation, QoL quality of life

Another important diagnostic consideration is that IBS-C appears to present with distinct microbial patterns, such as a reported higher abundance of Oscillospira and Methanobrevibacter smithii; however, similar to multiple microbiome studies, data interpretation is limited by numerous confounders (e.g., diet, medications, comorbidities, stool collection methods) [21–24]. Breath testing may be considered in patients with severe or refractory symptoms and in those who have risk factors for intestinal microbial overgrowth (e.g., abnormal small intestinal motility) [25, 26]. Although small intestinal bacterial overgrowth (SIBO) and intestinal methanogen overgrowth (IMO) can both cause bothersome GI symptoms including bloating, their clinical associations differ. For example, IMO is more strongly associated with constipation, whereas SIBO is more commonly associated with diarrhea [27–30]. In patients with IBS-C and IMO, M. smithii produces excess methane, contributing to bloating and worsening constipation [23, 31, 32]. Importantly, the clinical value of breath testing remains under debate, and it is unclear whether methanogens are mechanistically involved in constipation or are simply epiphenomena associated with the condition in this population.

Illustrative Case Vignettes

Three hypothetical cases are provided to illustrate scenarios encountered in clinical practice (Fig. 3). Cases 1 and 2 depict contrasting patient journeys to an IBS-C diagnosis. Key takeaways from these two cases are that IBS-C is not a diagnosis of exclusion, and a confident positive diagnosis alongside patient education is important. Colonoscopy is not recommended in patients aged < 45 years without alarm features; anorectal physiology testing is recommended in patients with refractory constipation unresponsive to standard medical therapy [18].

Fig. 3.

IBS-C case vignettes. BID twice daily, HCP healthcare provider, GI gastrointestinal, IBS irritable bowel syndrome, IBS-C irritable bowel syndrome with constipation, IMO intestinal methanogen overgrowth, OTC over the counter, PEG polyethylene glycol, QoL quality of life, TID three times daily

In case 1, the patient’s experience illustrates potential pitfalls in the journey to an IBS diagnosis, including unnecessary testing and inadequate counseling regarding IBS—leading to the question: how could this patient’s diagnostic journey have been improved?

In contrast, case 2 illustrates a shorter journey to an IBS-C diagnosis. In case 1, a timely diagnosis and patient education may have prevented doubts related to the diagnosis. Additionally, understanding that IBS subtypes can change over time in some patients might have been reassuring. Asking open-ended questions is valuable to gain an understanding of the patient’s concerns, most bothersome symptoms, and goal(s) for the appointment. While some patients are satisfied knowing that there is no organic pathology underlying their symptoms, many may be anxious to better understand IBS pathophysiology and how to improve symptoms. To set appropriate expectations, patients should be counseled that IBS is a chronic, but not life-threatening, condition, and even with treatment, symptoms may not completely resolve and may recur or fluctuate in intensity or degree of bother, without apparent cause. As well, HCPs should collaborate with the patient when developing an individualized treatment plan.

The third case (case 3) highlights the importance of considering IMO in patients with IBS-C as a potential cause or contributing factor when symptoms persist despite use of guideline-recommended therapies (e.g., prosecretory agents). In such refractory cases of IBS-C with bloating, breath testing serves as a valuable, noninvasive diagnostic tool. According to the North American Consensus publication on hydrogen and methane-based breath testing in GI disorders, a methane level of ≥ 10 parts per million at any point during the breath test is the recommended diagnostic threshold for IMO [28]. For patients with a positive methane breath test indicating IMO, combination antibiotic therapy is preferred over monotherapy, based on limited available evidence [26, 33]. In case 3, the combination of rifaximin plus neomycin for 2 weeks was based on findings from a small randomized, double-blind, placebo-controlled trial of 32 patients with IBS-C and IMO, which reported significant improvement in symptoms of constipation and bloating (both P < 0.05) [31]. However, neomycin should be used with caution, in light of the limited, mixed evidence supporting its use in IBS-C and IMO and its known risks of ototoxicity and nephrotoxicity. This underscores the importance of a thorough, informed risk–benefit discussion between the HCP and the patient.

IBS-C Symptoms and Treatment

Constipation and Abdominal Pain

Treatment

To improve global symptoms of IBS, the ACG recommends nonpharmacologic approaches, including the low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet and brain–gut behavioral therapies (e.g., gut-directed cognitive behavioral therapy or hypnotherapy) [18]. Gut microbiota dysbiosis and/or visceral hypersensitivity may underlie the GI symptoms associated with FODMAP exposure [34, 35]. Tricyclic antidepressants (TCAs) are strongly recommended based on a moderate quality of evidence [18]. The potential role of newer neuromodulators (e.g., serotonin-norepinephrine reuptake inhibitors) is discussed in a subsequent section. Although the OTC osmotic laxative PEG is administered for occasional constipation, the ACG recommends against its use for relief of global IBS symptoms, including abdominal pain [18].

Pharmacologic treatments specifically indicated for IBS-C and strongly recommended by the ACG for overall symptom improvement include the guanylate cyclase C agonists plecanatide and linaclotide and the chloride channel activator lubiprostone (restricted indication: adult women with IBS-C) [18]. The sodium/hydrogen exchanger 3 (NHE3) inhibitor tenapanor is also indicated for treatment of IBS-C, but was approved after the ACG guideline publication. The molecular mechanisms of action for each of these treatments result in increased fluid in the intestinal tract, which promotes motility [36, 37]. Additionally, linaclotide, plecanatide, and tenapanor may reduce visceral hypersensitivity [37, 38]. Modulation of visceral hypersensitivity may help normalize altered gut–brain signaling in IBS [39, 40]. Emerging evidence also suggests modulation of the gut microbiota may play a role in the therapeutic mechanism of IBS-C treatments [41]. It is important for primary care HCPs to be familiar with the US Food and Drug Administration (FDA)-approved options for the management of IBS-C, and pivotal phase 3 trial data are briefly summarized below.

In two identically designed phase 3 randomized, double-blind, placebo-controlled trials of plecanatide 3 mg once daily (indicated dose) and 6 mg once daily in patients with IBS-C, the primary efficacy endpoint was the percentage of responders, defined as ≥ 30% reduction from baseline in worst abdominal pain and an increase of ≥ 1 complete spontaneous bowel movement (CSBM)/week from baseline in the same week for ≥ 6 of the 12 weeks of treatment [42]. In both trials, the percentage of responders in both plecanatide groups was significantly higher versus the placebo groups (21.5–30.2% vs 14.2–17.8%, respectively; all P < 0.01) [42]. A 12-week and a 26-week phase 3, double-blind, placebo-controlled trial assessed linaclotide 290 µg daily in patients with IBS-C [43, 44]. Response was defined as ≥ 30% improvement from baseline in the average daily worst abdominal pain score and an increase of ≥ 1 CSBM from baseline in the same week for ≥ 6 of 12 weeks of treatment [43, 44]. In both trials, a significantly greater percentage of patients in the linaclotide group were responders versus in the placebo group: 33.6% vs 21.0%, respectively, in the 12-week trial and 33.7% vs 13.9%, respectively, during the first 12 weeks of the 26-week trial (both P < 0.0001) [43, 44]. Two 12-week, phase 3, randomized, double-blind, placebo-controlled trials of lubiprostone 8 µg twice daily in patients with IBS-C (91.6% female) evaluated responder rates (response defined as reporting symptoms to be at least moderately relieved for all 4 weeks or significantly relieved for ≥ 2 of 4 weeks, without ratings of moderate or severe worsening) [45]. A significantly higher percentage of patients treated with lubiprostone were responders versus placebo (17.9% vs 10.1%, respectively; P = 0.001). Constipation severity was significantly improved in the lubiprostone compared with the placebo group in months 1, 2, and 3 [45]. A 12-week and a 26-week phase 3, double-blind, placebo-controlled trial assessed response to tenapanor 50 mg twice daily in patients with IBS-C [46, 47]. Response was defined as a ≥ 30% reduction from baseline in the average weekly worst abdominal pain score and an increase of ≥ 1 CSBM/week from baseline in the same week for ≥ 6 of 12 weeks of treatment [46, 47]. A significantly greater percentage of patients treated with tenapanor were responders versus placebo in the 12-week trial (27.0% vs 18.7%, respectively; P = 0.02) and during the first 12 weeks of the 26-week trial (36.5% vs 23.7%, respectively; P < 0.001) [46, 47].

Abdominal Discomfort

Although abdominal discomfort is no longer part of the most recent Rome criteria for IBS, data support that most patients with IBS perceive abdominal pain and abdominal discomfort as different symptoms. In a US-based survey, abdominal discomfort was most frequently reported as the “symptom experienced the most in the past 7 days” [8]. Overall, among 910 respondents with IBS-C, 71.0% reported experiencing abdominal discomfort; among those reporting this symptom, 45.4% reported experiencing abdominal discomfort “all” or “most” of the time [8]. Abdominal discomfort was ranked as the third most bothersome symptom [8].

Treatment Effects: Abdominal Discomfort

Abdominal discomfort was evaluated as an endpoint in several clinical trials for several FDA-approved medications for IBS-C. In plecanatide phase 3 trials, significant improvements in abdominal discomfort versus placebo were evident by week 2 in both the 3-mg and 6-mg dose groups, with improvement maintained over 12 weeks of treatment (P < 0.001) [42]. For linaclotide, significantly greater mean reductions from baseline in abdominal discomfort score (improvement) were observed versus placebo in both the 12-week (P < 0.0001) and 26-week (P < 0.0001) phase 3 trials [43, 44]. In the lubiprostone phase 3 trials, abdominal discomfort was assessed as a combined secondary endpoint with abdominal pain, with significantly greater improvements versus placebo in months 2 and 3 (P ≤ 0.05), but not in month 1 [45]. For tenapanor, the percentage of abdominal discomfort responders (≥ 30% improvement from baseline in mean weekly severity score for ≥ 6 of 12 weeks) was significantly higher versus placebo in the 12-week phase 3 trial (P = 0.006); data were not reported in the 26-week trial [46, 47].

Bloating

Bloating is a common symptom in IBS-C [7, 8, 15] and can be challenging to treat [48]. In a US-based survey, among 910 respondents with IBS-C, 58.2% reported abdominal bloating, with 59.1% reporting that bloating was among symptoms leading them to take a medication [8]. In a Canadian survey of 467 people with IBS-C, 28% reported experiencing bloating “always” in the previous 3 months [15]. The QoL impact of bloating was assessed in an Italy-based survey of 2203 patients with either IBS-C or CIC: bloating was associated with lower QoL, even after adjustment for potential confounders [49]. In some patients, other conditions such as motility disorders (e.g., dyssynergic defecation) or intestinal bacterial overgrowth may contribute to the co-occurring symptoms of constipation with bloating and should be considered [25, 29, 50]. Note that many patients complain of both bloating (the perception of abdominal pressure) and distention (a physical increase in abdominal girth) [48]. To date, no pharmacotherapy trials have specifically evaluated abdominal distention as a primary or secondary endpoint.

Treatment Effects: Bloating

A meta-analysis of 13 randomized, placebo-controlled IBS-C trials concluded that prosecretory agents were significantly more effective than placebo for treating abdominal bloating experienced by patients with IBS-C [51]. In plecanatide phase 3 trials, significant improvement in abdominal bloating intensity was observed with plecanatide versus placebo after 1 week of treatment and maintained over a 12-week treatment period (P < 0.001) [42]. Mean improvements in abdominal bloating with linaclotide versus placebo were significant in both the 12-week (P < 0.0001) and the 26-week phase 3 trials (P < 0.0001) [43, 44]. In lubiprostone phase 3 trials, mean improvements in abdominal bloating were significantly greater versus placebo in month 2 (P = 0.04), but not in months 1 and 3 [45]. In the 12-week tenapanor trial, the percentage of bloating responders (≥ 30% improvement from baseline in mean weekly severity score for ≥ 6 of 12 weeks) was significantly higher for tenapanor versus placebo (P = 0.01); data were not reported in the 26-week trial [46, 47].

Straining

Straining during a bowel movement was reported by 61.1% of 910 patients self-reporting IBS-C in the US-based survey [8]. Among 885 respondents ranking the most bothersome IBS-C symptoms, straining was the second most bothersome symptom after abdominal pain, with 16.8% identifying straining as their most bothersome symptom [8].

Treatment Effects: Straining

Several pharmacologic treatments approved for IBS-C have demonstrated improvement in straining. In the plecanatide phase 3 trials, significant reductions in straining were reported with both the 3-mg and 6-mg doses versus placebo (P < 0.001) [42]. Improvements in straining were apparent by week 1 and were maintained over the 12-week course of treatment in both trials [42]. For linaclotide, mean improvements in straining versus placebo were significant in both the 12-week (P < 0.0001) and 26-week (P < 0.0001) phase 3 trials [43, 44]. In the lubiprostone phase 3 trials, mean improvements in straining were significantly greater versus placebo in months 1 and 2 (P ≤ 0.01), but not month 3 [45]. There was no significant change from baseline in straining score at week 12 with tenapanor compared with placebo in a phase 3 trial (P = 0.66); data were not reported in the 26-week trial [46, 47].

Multisymptom Efficacy Endpoints in IBS-C

Given the prevalence and impact of symptoms such as abdominal discomfort, bloating, and straining in IBS-C, there is a clinical rationale for efficacy assessments that encompass simultaneous improvement in multiple symptoms beyond the traditional cardinal symptoms of abdominal pain and reduced bowel movement frequency. Several studies have embraced this concept and reported findings using broadened composite efficacy endpoints [52, 53]. A trisymptom composite endpoint of abdominal pain, bloating, and bowel movement frequency was evaluated in a pooled post hoc analysis of the two plecanatide phase 3 trials in adults aged 18–40 years who had IBS-C with bloating [53]. Response was defined as simultaneous improvement from baseline in all three symptoms, with several composite criteria thresholds analyzed (i.e., ≥ 2-point decrease or ≥ 30% or ≥ 40% improvement in abdominal pain and bloating and an increase of ≥ 1 or ≥ 2 CSBMs in the same week for ≥ 6 of 12 weeks). A significantly greater percentage of patients treated with plecanatide 3 mg versus placebo were responders across a range of stringent response thresholds (16.0–23.3% vs 7.2–13.4%; all P ≤ 0.002). A significantly higher percentage of patients were trisymptom responders in the plecanatide versus placebo groups regardless of baseline bloating intensity (mild; moderate to severe) across most response thresholds. Another analysis of pooled phase 3 plecanatide data investigated a composite endpoint of abdominal pain and bloating, with responders defined as those with ≥ 30% improvement from baseline to week 12 in both symptoms [54]. A significantly greater percentage of patients treated with plecanatide 3 mg were composite responders versus placebo in both moderate-to-severe bloating (33.6% vs 26.8%, respectively; P = 0.02) and mild bloating (38.4% vs 27.2%, respectively; P = 0.03) subgroups [54].

A randomized, double-blind, placebo-controlled trial of linaclotide evaluated change in an “abdominal score” that was based on a composite endpoint of abdominal bloating, discomfort, and pain—each assessed using an 11-point scale [52]. The improvement (decrease) from baseline in abdominal score was found to be significantly greater in patients treated with linaclotide versus placebo (− 1.9 vs − 1.2, respectively; P < 0.0001). An abdominal score (composite of abdominal bloating, discomfort, and pain) with symptoms assessed daily using an 11-point scale was also utilized in a pooled post hoc analysis of three randomized controlled tenapanor trials [55]. During 12 weeks of treatment, the mean decrease from baseline in abdominal score was greater for tenapanor versus placebo (− 2.7 vs − 2.1, respectively; P < 0.0001) [55]. Tenapanor also decreased abdominal symptoms (composite of pain, bloating, and discomfort) regardless of changes in CSBM frequency [39].

Additional Clinical Considerations

Role of Neuromodulators

Beyond the targeted, bowel-specific medications indicated for IBS-C that are detailed above, neuromodulators can play an adjunctive role [56]. They should be considered for patients whose IBS-related symptoms persist despite first-line treatments indicated for IBS-C. Neuromodulator use is common in contemporary IBS management: in a survey of 525 US-based gastroenterologists, more than half (55.2%) rated central neuromodulators as “extremely/very important” for treating IBS, with median reported use in 21–30% of their patients [57]. Neuromodulators act on the brain–gut axis and have multiple effects, including reducing visceral hypersensitivity, altering gut motility/intestinal transit, and enhancing neurogenesis [58]. Consequently, they may improve global symptoms of IBS and address common co-occurring psychiatric conditions (e.g., anxiety), although effects vary by drug class and more robust clinical research is needed [56, 59–61].

In the largest randomized controlled trial evaluating TCAs for IBS, the ATLANTIS (Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment) trial (n = 463; 17% IBS-C) reported that low-dose amitriptyline (10–30 mg/day) led to significantly greater reductions in the Irritable Bowel Syndrome Severity Scoring System score and higher rates of adequate symptom relief at 6 months versus placebo (P < 0.05 for both) [62]. However, because TCAs may worsen constipation, they are generally not considered for patients with IBS-C [58, 59]. For IBS-C specifically, a small randomized trial of 44 patients found that the selective serotonin reuptake inhibitor (SSRI) fluoxetine 20 mg daily significantly improved constipation, abdominal discomfort, and bloating after 12 weeks of treatment, compared with placebo (P < 0.05 for all comparisons) [63]. However, SSRIs do not typically improve the pain in IBS-C and are not recommended for patients whose predominant symptom is pain [58, 59].

An important consideration when selecting neuromodulators for treatment of IBS-C is the potential for certain classes to exacerbate constipation [58]. As noted above, tertiary amine TCAs (e.g., amitriptyline, imipramine) should be avoided because of their pronounced anticholinergic effects [58, 59]. Classes with a lower risk of constipation that are considered more suitable for patients with IBS-C include serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) and secondary amine TCAs (e.g., desipramine, nortriptyline) [58, 59]. Although SSRIs are not appropriate for patients for whom the predominant symptom is pain, they may have a role in some individuals with IBS-C, particularly when anxiety states (e.g., visceral anxiety) are present [59]. Mirtazapine, a noradrenergic and specific serotonergic receptor antagonist is considered for IBS-D [64–66] but, based on a case study, it might improve constipation in patients with IBS mixed type and a psychiatric comorbidity [67].

Collaborative Patient–HCP Relationship

An early and confident IBS-C diagnosis based on targeted investigation and educational support focused on patient interest may help facilitate diagnosis acceptance [68]. A collaborative patient–HCP relationship is a foundation for effective IBS-C management, with key components including active listening, empathy, establishing trust, validation of the patient’s concerns, and a nonjudgemental patient-centric approach [69]. Patient education ideally includes confident affirmation of their positive IBS-C diagnosis as a real condition and conveying that treatment goals include reducing symptom burden, increasing a sense of control, and improving healthcare-related QoL [69]. For effective management of IBS-C symptoms, it is essential to identify what the patient perceives to be their most bothersome symptoms and ascertain symptom intensity and impact [69]. It is also important to gain insight regarding factors that may exacerbate or alleviate symptom flares [69]. Reviewing prescription and OTC medications and dietary supplements is helpful because some may contribute to IBS symptoms. For example, constipation may be worsened by certain products, including anticholinergics, calcium and iron supplements, diuretics, and opioid analgesics [70]. Some patients may benefit from professional dietary management (e.g., single-food avoidance, low FODMAP diet, gluten-free diet) [4, 18] and/or brain–gut behavioral interventions (e.g., cognitive behavioral therapy, gut-directed hypnotherapy) [18, 71, 72].

Conclusions

Although constipation and abdominal pain are the defining (cardinal) IBS-C symptoms, patients with this condition commonly experience a range of additional bothersome symptoms, including abdominal discomfort, bloating, and straining. Given the frequency and negative impacts of these other IBS-C symptoms, there is a clinical rationale for broadened composite efficacy endpoints for treatment evaluation. Several pharmacologic agents are indicated for the treatment of IBS-C: linaclotide, lubiprostone, plecanatide, and tenapanor. Several of these have demonstrated improvements in both individual symptoms and novel multisymptom endpoints. An integrated approach to treatment of IBS-C, particularly for patients who continue to experience symptoms after first-line therapy with secretagogues or NHE3 inhibitors, may include the use of neuromodulators to address visceral hypersensitivity and/or targeted treatment in patients with IMO. Additionally, nonpharmacologic strategies, such as dietary interventions and brain–gut behavioral therapies, may provide further benefit. Optimal management of IBS-C involves a timely and positive IBS-C diagnosis based on targeted evaluation, collaborative patient–HCP engagement, and a personalized treatment plan that targets the patient’s most bothersome symptoms. Therapeutic options should be reviewed and selected through a shared decision-making process between the patient and HCP.

Author Contributions

Eric D. Shah, Amol Sharma, Nijmeh Curren, Adam P. Laitman, and Kyle Staller were involved with developing the manuscript concept, had access to all data presented, and were involved with drafting and critically revising the manuscript and preparing and approving the manuscript for final submission. All authors agree to take responsibility and accountability for the contents of the manuscript.

Funding

Salix Pharmaceuticals provided funding to Synchrony Medical Communications, LLC, for its technical editorial support in development of this narrative review. Salix Pharmaceuticals also provided payment for the journal’s open access and rapid service fees. The authors did not receive any financial compensation for narrative review development. Nijmeh Curren and Adam P. Laitman received salaries as employees of Salix Pharmaceuticals. Other than these authors, Salix Pharmaceuticals did not actively contribute to content or have a role in the decision to submit but reviewed for medical accuracy.

Data Availability

Data sharing is not applicable to this article, as no datasets were generated or analyzed during the current study.

Declarations

Conflicts of Interest

Eric D. Shah reports being a consultant for AbbVie, Ardelyx, Cook Group, Laborie Medical Technologies, Mahana Therapeutics, Mylan (Viatris), NeurAxis, Salix Pharmaceuticals, Sanofi, and Takeda Pharmaceutical; holding stock in NeurAxis; and having a patent with the Regent of the University of Michigan. Amol Sharma is a consultant for Atmo Biosciences and has received research support from Vibrant Gastro. Nijmeh Curren and Adam P. Laitman are employees of Salix Pharmaceuticals. Kyle Staller has served as a consultant to Anji Pharmaceuticals, Ardelyx, Gemelli Biotech, Laborie Medical Technologies, Mahana Therapeutics, ReStalsis Health, Salix Pharmaceuticals, and Takeda Pharmaceutical, and has received research support from Ardelyx and ReStalsis Health.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.