Irritable bowel syndrome with constipation: a European-focused systematic literature review of disease burden

Abstract

Objective:

To conduct a systematic literature review to assess burden of disease and unmet medical needs in patients with irritable bowel syndrome (IBS) with constipation (IBS-C), with a focus on five European countries (France, Germany, Italy, Spain, UK).

Methods:

MEDLINE, EMBASE, and grey literature searches were carried out using terms for IBS and constipation, to identify studies reporting epidemiological, clinical, humanistic, or economic outcomes for IBS-C, published between 2000 and 2010.

Results:

Searches identified 885 unique abstracts and 33 supplementary articles, of which 100 publications and six grey literature sources met the inclusion criteria. Among patients with IBS, the prevalence estimates of IBS-C ranged from 1 to 44%. Co-morbid conditions, such as personality traits, psychological distress, and stress, were common. Patients with IBS-C had lower health-related quality-of-life (HRQoL) compared with the general population, and clinical trials suggested that effectively treating IBS-C improves HRQoL. The European societal cost of IBS-C is largely unknown, as no IBS-C-specific European cost-of-illness studies were identified. Two cost analyses demonstrated the substantial societal impact of IBS-C, including reduced productivity at work and work absenteeism. Guidelines offered similar recommendations for the diagnosis and management of IBS; however, recommendations specifically for IBS-C varied by country. Current IBS-C treatment options have limited efficacy and the risk:benefit profile of early 5-HT₄ agonists restricts clinical use.

Conclusions:

This systematic review indicates a clear need for European-focused IBS-C burden-of-disease and cost-of-illness studies to address identified evidence gaps. There is a need for new therapies for IBS-C that are effective, well tolerated, and have a positive impact on HRQoL.

• Irritable bowel syndrome
• Constipation
• Epidemiology
• Clinical
• Economic
• Disease burden
• Systematic review

Introduction

Irritable bowel syndrome (IBS) is a common, functional gastrointestinal (GI) disorder characterized by chronic symptomatic episodes of abdominal pain or discomfort related to abnormal bowel movements, followed by periods of improvement and fewer, less severe, bowel symptoms1. There is little consensus on the pathophysiology of IBS; however, it has been proposed that it results from a complex interaction of altered gut motility and transit, increased sensitivity of the colon or intestine, and psychological factors such as psychological distress, childhood trauma, and recent environmental stress2,3.

A systematic review and meta-analysis reported the global prevalence of IBS in 80 separate study populations containing 260,960 subjects4. Pooled prevalence in all studies was 11.2% (95% confidence interval [CI] = 9.8, 12.8)4. The prevalence varied according to geographical location, including a prevalence of 12.0% (95% CI = 9.0, 15.0) in Northern Europe and 15.0% (95% CI = 11.0, 20.0) in Southern Europe4. IBS is more common in women than men, and people younger than 50 years of age are more likely to be affected than those over 505,6. Additional risk factors may include certain foods, co-morbid psychological disorders, GI-related factors, smoking, and family history of IBS7–10.

The diagnosis of IBS is based on patient-reported symptoms. According to the latest Rome III diagnostic criteria there are five sub-types of IBS: IBS with constipation (IBS-C); IBS with diarrhoea (IBS-D); IBS with mixed constipation and diarrhoea (IBS-M); IBS-M with alternating constipation and diarrhoea (IBS-A); and unsubtyped IBS (IBS-U)1,11–13. To meet the Rome III criteria, patients’ symptoms must have persisted for at least 6 months and be present at least 3 days per month before diagnosis13.

IBS-C is the focus of the present review. It is characterized by hard or lumpy stools for 25% or more of bowel movements and loose or watery stools for fewer than 25% of bowel movements, with fewer than three bowel movements per week13. Symptoms of IBS-C include abdominal pain, discomfort, and bloating12. Furthermore, individuals with IBS-C often experience distress, dysfunction, and reduced productivity associated with the painful bowel disorder14,15. Therefore, from a societal perspective, cumulative work loss and healthcare resource utilization associated with IBS-C is likely to be significant16,17. Therapeutic targets for IBS-C have focused on stimulation of GI motor function, with the treatment goal being to improve bowel function and alleviate abdominal symptoms, especially pain and discomfort. However, currently, there are few effective and tolerable treatment options for IBS-C1,18, which may add to the economic burden of IBS-C.

Recent IBS review articles focus on discussing current pharmacological treatment developments for IBS-C19–21 or do not separate IBS-C from IBS22; there are a limited number of evidence-based reviews focusing specifically on the burden and management of IBS-C. Therefore, given that IBS-C accounts for one-third of patients with IBS5 and is likely to be associated with a major impact on patient health-related quality-of-life (HRQoL) and cost to society, we conducted a systematic review of the literature pertaining to the epidemiological, clinical, economic, and humanistic impact of IBS-C, to assess the burden of disease and unmet medical needs of patients with IBS-C. This review focused on five European countries (France, Germany, Italy, Spain, and the UK), representing almost two-thirds of the total population of Europe23, as these countries often act as a reference for the other smaller European countries with regards to medical guidelines. Our aim was to improve understanding of the impact of IBS-C on patients and healthcare systems in Europe and identify needs currently unmet by treatment options.

Methods

Inclusion/exclusion criteria for the systematic literature review

Studies meeting all of the following criteria were eligible for inclusion in the systematic review: primary research studies published between January 2000 and December 2010 including more than 20 human subjects or review articles published between December 2007 and December 2010; studies with abstracts; studies reporting epidemiological, clinical, humanistic, or economic outcomes for IBS-C; and studies published in the English language. Studies that did not specify a population with the IBS sub-type IBS-C were excluded. In vitro, animal, foetal, molecular, genetic, and pharmacokinetic or pharmacodynamic studies were also excluded. Topics with geographic specificity (i.e. epidemiology, guidelines, practice patterns, and economic outcomes) were limited to studies in the five European countries of interest (France, Germany, Italy, Spain, and the UK).

Literature search

Systematic literature search

Published articles potentially reporting the disease burden of IBS-C were retrieved by searching MEDLINE and EMBASE. Searches were carried out in March 2011. Search strategies included terms for IBS and constipation. Specific limits for retrieving English-language studies conducted in humans published between January 2000 and December 2010 were applied to the searches. Additionally, bibliographies of review articles identified by the search were examined for relevant studies.

Abstracts were initially screened for suitability according to the specified inclusion/exclusion criteria, to determine whether the full-text publication should be retrieved for further review. A second reviewer screened 100% of the abstracts to minimize bias and ensure accuracy. Full-text publications were then examined for relevance for inclusion in the review by two reviewers. Any disagreements between the reviewers were resolved by consensus. Positive exclusion was employed in the screening of articles so that only those that did not exhibit one or more of the inclusion criteria were excluded from the review. For outcomes for which the systematic literature review identified a lack of European studies with IBS-C specific data, European and non-European studies in patients with IBS (not specifically IBS-C) were included in the review.

Targeted non-English language literature search

In addition to the systematic searches described above, supplementary targeted literature searches of MEDLINE and EMBASE were performed to identify non-English language primary research studies, from France, Germany, Spain, and Italy, using the same criteria as the systematic literature search. Full-text publications were reviewed by native-language speakers to determine their relevance for inclusion in the review.

Grey literature search

Manual grey literature searches of relevant websites (gastroenterology societies, health organizations, health technology assessment bodies, clincaltrials.gov, and the Cochrane Library and Database of Systematic Reviews) were also performed to identify information on the burden of illness (including treatment guidelines) for IBS-C in France, Germany, Italy, Spain, and the UK, which was not published in peer-reviewed, indexed, medical journals. A full list of the grey literature searched is included in the Online Appendix.

Results

The systematic literature search identified 885 unique abstracts that were screened to assess their suitability for inclusion in the review. The number of articles proceeding at each stage of the review and reasons for exclusion are summarized in Figure 1. A total of 279 full-text publications from the systematic literature search met the inclusion criteria for further review. Twenty non-English language articles were identified from the targeted literature search and 13 documents were retrieved from the grey literature searches. One hundred full-text publications from the systematic literature review and six documents from the grey literature search were selected for inclusion in the review. No publications from the non-English language search met the inclusion criteria.

Figure 1.  Number of articles proceeding at each stage of the systematic review. IBS-C, irritable bowel syndrome with constipation.

The most common topics reported in the studies were treatment (38%) and definition/aetiology/diagnosis (32%) (Table 1). In the current article, we focus on reporting data on burden of illness, humanistic burden, economic burden, and treatment of IBS-C. Articles relating to definitions, aetiology and diagnosis are not discussed in detail1,7,11–13,24–54.

Table 1.  Total number (%) of studies reporting data for different IBS-C topics.*

IBS-C topic	Number (%) of studies
Treatment	42 (38%)
Definition/aetiology/diagnosis	36 (32%)
Humanistic burden	18 (16%)
Burden of illness	8 (7%)
Economic burden	8 (7%)

*Total number of studies is >106, as some publications report data for multiple IBS-C topics.

IBS-C, irritable bowel syndrome with constipation.

Burden of illness

Epidemiology

The prevalence of IBS-C among patients with IBS was reported in four studies, ranging from 1 to 24.1% in the UK43,55, to 34.6% in France27, and 44% in Spain56. No studies reporting the incidence of IBS-C were identified.

Risk factors

Two studies in patients with IBS reported personality traits, psychological distress, and stress as possible risk factors for IBS-C, compared with individuals with IBS-D or IBS-A57 or non-IBS controls58. However, a conflicting study reported a greater prevalence of psychological and extra-intestinal symptoms in patients with IBS-A compared with those with IBS-C or IBS-D59. In addition, a case-control study of 42 patients with IBS and 25 healthy controls demonstrated that a potential molecular biomarker, p11 (calpactin I light chain), was elevated in patients with IBS-C60.

Humanistic burden

Between 2000 and 2010, 18 studies (most of which were prospective) have examined HRQoL and health states in patients with IBS-C61–78. Instruments used to assess HRQoL included: general scales, such as the Short Form (SF)-36; GI disease scales, such as the GI Quality-of-Life (GIQLI) questionnaire; and disease-specific scales, including the IBS Quality-of-Life (IBS-QOL) and the Functional Digestive Disorders Quality-of-Life (FDDQL) questionnaires.

The IBS-QOL was the most frequently used HRQoL instrument, administered in eight of 18 studies61,62,64,68–71,77. Humanistic studies using the IBS-QOL to evaluate HRQoL in patients with IBS-C are presented in Table 2. Survey studies demonstrated that patients with IBS-C have diminished HRQoL compared with the general population, and clinical trials suggested that effectively treating IBS-C symptoms improves HRQoL. Five studies compared HRQoL impairment between IBS sub-types61,63,73,74,78. However, results were conflicting and no conclusion could be drawn as to whether patients with IBS-C have more or less HRQoL impairment than those with other IBS sub-types.

Table 2.  Summary of humanistic studies using the IBS-QOL to evaluate HRQoL in patients with IBS-C.

Authors (year)	Study design and patients	Intervention	HRQoL outcomes	Conclusion
Amouretti et al.61 (2006)	Prospective survey study of QoL in French patients (n = 253, mean age 48.3 years, 76% female) with IBS. Sample included: 26% IBS-C, 28% IBS-D, and 46% IBS-A.	None	Women had significantly poorer HRQoL than men in all IBS-QOL domains except sleep.	IBS has a significant impact on patient HRQoL. Specific characteristics (gender, symptom severity, and time since onset of symptoms) were predictive of greater HRQoL impairment.
Cain et al.62 (2006)	Secondary analysis of three studies (conducted between 1997 and 2004) evaluating the impact of IBS on QoL in women (n = 242, mean age 33 years) with IBS. Sample included: 26% IBS-C, 37% IBS-D, and 34% IBS-A.	None	Most frequent symptom: intestinal gas (on 74% of days, with moderate/worse severity 27% of days). Abdominal pain was most strongly related to IBS-QOL score and diary-reported life-impact variables, including interference with relationship, work, and other plans. Correlations of IBS symptoms with life-impact variables did not differ significantly in IBS sub-groups.	While intestinal gas was the most frequent symptom, abdominal pain was the most disruptive symptom with the largest impact on QoL. Agents that effectively treat IBS symptoms will likely impact QoL.
Drossman et al.64 (2009)	Pooled analysis of efficacy/safety from two phase III, 12-week RCTs of lubiprostone. IBS-QOL outcomes were evaluated at baseline, week 4 and week 12. Adults (n = 1171, mean age 46.6 years) with IBS-C.	Lubiprostone 8 μg daily vs placebo	Overall analysis of IBS-QOL scores indicated a trend towards greater improvement with lubiprostone at week 12 (p = 0.066). Sub-domains of ‘body image’ and ‘health worry’ were significantly improved in the lubiprostone group at week 12 compared with baseline (p ≤ 0.025). Clinically meaningful changes (>14 points) in IBS-QOL domains of social reaction, food avoidance, health worry, body image, and dysphoria were observed in the lubiprostone group.	Lubiprostone was associated with a trend towards improved QoL. Significant improvements were observed in ‘body image’ and ‘health worry’ sub-domains compared with placebo.
Hawkes et al.68 (2002)	8-week RCT for the safety/efficacy of naloxone in IBS-C. Adults (n = 28 [22 females], mean age 45.4 years) with IBS-C or IBS-A.	Naloxone 20 mg daily vs placebo	At baseline, mean QoL scores were lower in the placebo group than in the treatment group. Scores for sleep and sexual domains were significantly lower (p = 0.05 and p = 0.03, respectively). During the study, there were trends of improvement across all but one domain in both placebo and treatment groups. Naloxone improved all nine QoL domains from baseline, with greater improvement than placebo in emotional, mental health, energy, physical functioning, food, social role, and physical role.	Naloxone is well tolerated and beneficial in patients with IBS-C, although larger clinical trials are needed to provide sufficient statistical power to assess efficacy.
Johanson et al.69 (2008)	3-month, multi-centre RCT evaluating the safety/efficacy of lubiprostone. Changes in QoL were assessed (secondary end-point) at weeks 4 and 12. Adults (n = 195, age range 18–80 years, 90% female) with IBS-C.	Lubiprostone 16 µg, 32 µg, or 48 µg daily vs placebo	No significant trend in QoL related to lubiprostone. The sub-domain ‘health worry’ score showed significant increase from baseline at week 4 (baseline placebo value was 45.3 and lubiprostone value range was 37.7–44.4; week 4 values were placebo 53.7 and lubiprostone 59.5–66.4, p = 0.021) and week 12 (placebo 58.5 and lubiprostone 61.5–66.1, p = 0.041). Patients receiving lubiprostone 48 µg reported significant improvements in ‘health worry’ at 4 and 12 weeks from baseline (p = 0.004 and p = 0.021, respectively).	Lubiprostone may impact QoL in patients with IBS-C; however, further trials are necessary.
Johnston et al.70 (2010)	12-week, multicentre RCT evaluating efficacy/safety of linaclotide. Adults (n = 420, mean age 44.4 years, 92% female) with IBS-C.	Linaclotide 75, 150, 300, or 600 μg daily vs placebo	Differences in IBS-QOL at 12 weeks were not significant from placebo for any dose, but IBS-QOL scores showed clinically meaningful (≥14-point) improvement in more than one-third of patients in all treatment groups. Specifically, 37% of patients treated with linaclotide had a change from baseline in overall IBS-QOL score of ≥14 points. Linaclotide 300 μg and 600 μg significantly improved the IBS-SSS QoL item (p < 0.01 and p < 0.05 vs placebo, respectively).	Some improvements in QoL were observed for all linaclotide treatment groups, although differences in overall scores from baseline were not significant. These, along with clinical findings, support the effect of linaclotide in IBS-C.
Lembo et al.71 (2010)	12-week multi-centre RCT evaluating efficacy/safety of renzapride in women with IBS-C. Adult females (n = 1798, mean age 43.3 years).	Renzapride 4 mg once daily or 2 mg twice daily vs placebo	A modest improvement in IBS-QOL was observed in all three groups. No significant differences were present in the IBS-QOL sub-scales.	Given a limited increase in efficacy vs placebo and the incidence of ischaemic colitis, data suggest that the benefit:risk ratio of renzapride is insufficient to warrant further study in IBS-C.
Tack et al.77 (2005)	RCT evaluating safety/efficacy of tegaserod for IBS-C. Patients received treatment for 1 month; those showing full/partial response entered a treatment-free period. Upon symptom recurrence patients were retreated for another month. Adult females (n = 2660, age range 17–66 years) with IBS-C. Of 2135 patients (525 placebo) in the first treatment period, 1194 (250 placebo) entered the second treatment period.	Tegaserod 6 mg daily vs placebo	Tegaserod significantly improved QoL compared to placebo in the first treatment period (4 weeks) (p < 0.05).	Clinical benefits of tegaserod were associated with improvement in QoL and high satisfaction. Tegaserod may be useful for short term, repeated treatment in females with IBS-C.

HRQoL, health-related quality-of-life; IBS, irritable bowel syndrome; IBS-A, irritable bowel syndrome alternating; IBS-C, irritable bowel syndrome with constipation; IBS-D, irritable bowel syndrome with diarrhoea; IBS-QOL, Irritable Bowel Syndrome Quality-of-Life instrument; IBS-SSS, Irritable Bowel Syndrome Symptom Severity Scale; QoL, quality-of-life; RCT, randomized controlled trial.

Economic burden

Two analyses of work productivity in women with IBS-C treated with tegaserod, based on the same randomized controlled trial, were the only articles presenting data on the economic burden of IBS-C in Europe identified by the systematic review (Table 3). Tegaserod was reported to improve work productivity compared with baseline and placebo, including less impairment while at work (presenteeism), absence from work (absenteeism), and activity impairment15,77. Reilly et al.15 concluded that most patients seeking treatment for IBS-C have work and daily activity impairments, and relieving multiple symptoms of IBS may enhance patient wellbeing and improve their productivity.

Table 3.  Studies evaluating economic burden associated with IBS-C.

Authors (year)	Study design	Treatment	Population	Outcomes
Reilly et al.15 (2005)	Analysis of data from an international, multi-centre RCT evaluating the efficacy/safety of tegaserod in women with IBS-C77. Work-related productivity and daily activity were assessed with the WPAI:IBS-C at weeks 2 and 4.	Tegaserod 6 mg twice daily vs placebo	Adult females with IBS-C (n = 2660) were randomized to receive tegaserod or placebo. Among all randomized patients, 1675 were employed (tegaserod [n = 1363], placebo [n = 312]) and completed the WPAI:IBS-C.	Overall, in employed women, tegaserod significantly reduced work and daily activity impairment at weeks 2 and 4 vs placebo. At week 4 tegaserod reduced absenteeism by 2.6% (p = 0.004), presenteeism by 5.4% (p < 0.0001), overall work productivity loss by 6.3% (p < 0.0001), and activity impairment by 5.8% (p < 0.0001) compared with baseline. In European countries, tegaserod only significantly reduced daily activity impairment at week 2 compared with placebo (p = 0.04). At week 4, tegaserod significantly reduced all work impairment measures, including absenteeism (p = 0.04), presenteeism (p = 0.05), overall work productivity loss (p < 0.003), and activity impairment (p = 0.004) compared with baseline. Conclusion: Tegaserod improves work and daily activity function in patients with IBS-C.
Tack et al.77 (2005)	Multi-centre prospective, randomized, double-blind, placebo-controlled, parallel-group study for the safety/efficacy of tegaserod in women with IBS-C. Work productivity was assessed using the WPAI:IBS-C at baseline and 2 weeks during both treatment periods.	Tegaserod 6 mg twice daily vs placebo	Adult females with IBS-C (n = 2660) were randomized to treatment for 1 month, and those showing full or partial response entered a treatment-free period. If symptoms recurred, patients were re-treated for another month. First treatment period: tegaserod (n = 1610), placebo (n = 525); second treatment period: tegaserod (n = 944), placebo (n = 250).	Patients treated with tegaserod had significantly improved WPAI:IBS-C scores vs placebo during the first treatment period (p < 0.05); significantly less presenteeism, less work impairment (presenteeism and absenteeism), and less activity impairment (all p < 0.05). Conclusion: Tegaserod may be associated with positive effects on work productivity in women with IBS-C.

IBS-C, irritable bowel syndrome with constipation; RCT, randomized controlled trial; WPAI:IBS-C, Work Productivity Activity Impairment for irritable bowel syndrome with constipation.

No studies presenting the cost of illness, cost analyses, or resource use in France, Germany, Italy, Spain, or the UK were identified by the systematic review; therefore, economic studies in patients with IBS (not specifically IBS-C) were included in the review. A systematic review of studies in the US and UK examining direct and indirect costs of IBS, not specifically IBS-C, identified 18 relevant studies published between 1991 and 200379. Estimates of the total annual direct cost per patient for IBS ranged from US$348 to US$8750 (2002 costs), and total annual indirect cost per patient ranged from US$355 to US$334479. Additionally, the average number of days off work per year due to IBS was reported as 8.5–21.6 days79. Based on a prospective survey carried out in 2000 in France, investigations and hospitalizations accounted for most of the medical costs in patients with IBS. The highest costs were reported among elderly patients or patients with severe IBS symptoms, mainly pain. Patients with IBS for fewer than 5 years reported more frequent use of supplementary investigations than did patients with IBS for more than 5 years80.

Treatment guidelines

Five clinical guidelines for the diagnosis and management of IBS published between 2000 and 2009 were identified by the systematic search, including: three UK guidelines from the National Institute for Health and Clinical Excellence (NICE) and the British Society of Gastroenterology (BSG)81–83; one from a pan-European group84; and one from the World Gastroenterology Organization (WGO)86. In addition, Spanish85 and German87 language guidelines, resulting from expert consensus groups, were identified as part of the grey literature search.

Taken together, these guidelines offered similar recommendations for the diagnosis and management of IBS; however, specific recommendations for the management of IBS-C varied by country. A summary of guideline recommendations for the treatment of IBS-C, identified by this systematic review, is provided in Figure 2. Increased dietary fibre was almost universally recommended for the treatment of IBS-C; however, pharmacological and non-pharmacological treatment recommendations varied.

Figure 2.  Summary of treatment guideline recommendations for the management of IBS-C. ‘Alarm’ symptoms, symptoms that may suggest organic disease; BSG, British Society of Gastroenterology; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FBC, full blood count; IBS-C, irritable bowel syndrome with constipation; NICE, National Institute for Health and Clinical Excellence; WGO, World Gastroenterology Organisation.

The use of psychological interventions (relaxation therapy, cognitive behavioural therapy, hypnotherapy) was described in most of the guidelines identified by the systematic review; however, recommendations differed between guidelines and there were no specific recommendations for patients with IBS-C81–83,85,86. In addition, the guidelines lacked information on complementary and alternative medicine approaches. Herbal medicines were only recommended in the most recent German guideline87. Similarly, probiotics, such as Bifidobacterium lactis, were suggested for IBS-C in the two most recent German and WGO guidelines85,87. Laxatives were specifically recommended in the NICE, WGO, Spanish, and German guidelines for IBS-C82,85–87, but discouraged in an older guideline84. The NICE and Spanish guidelines also recommended anti-spasmodic agents, such as otilonium bromide and mebeverine, to treat pain and constipation82,86. In addition, antidepressant use in IBS-C was described in three guidelines82,86,87. While the NICE guidelines recommended tricyclic antidepressants as second-line therapy for IBS-C82, the more recent German guideline advised against them as they are associated with constipation87.

Two agents targeted specifically at IBS-C, tegaserod (approval withdrawn in the US and Switzerland in 2007 and now only available in the US as an investigational new drug, with its use restricted to women under the age of 55 with a low cardiovascular safety risk) and lubiprostone (approved in the US and in Switzerland for the treatment of chronic constipation in adult patients and the treatment of IBS-C in women only), were described in three guidelines83,85,87; the most recent German and WGO guidelines recommended lubiprostone for IBS-C treatment85,87, and tegaserod was recommended as a second-line agent by the BSG83.

Non-pharmacological therapies

Non-pharmaceutical treatment options for IBS-C include herbal formulations, fibre, probiotics, or symbiotic formulations. Two studies identified by the systematic review evaluated the safety and efficacy of herbal formulations for the treatment of IBS-C, demonstrating a reduction in IBS-C symptoms without any serious adverse events88,89. Further studies identified showed that fibre90,91 and probiotics or symbiotic formulations67,92–95 may be beneficial to the symptoms of patients with IBS-C. No studies were identified by the systematic review that evaluated the safety and efficacy of psychological interventions for the treatment of IBS-C.

Pharmacological therapies

Although the clinical efficacy of laxatives for the treatment of IBS is well established82, no studies evaluating the safety and efficacy of laxatives in patients with IBS-C were identified by the systematic review. In addition, no studies that evaluated the safety and efficacy of anti-spasmodics for the treatment of IBS-C were identified.

While the potential role for antidepressant therapy has been noted for IBS, only one study was identified by the systematic review that evaluated the effect of antidepressant agents specifically on IBS-C. In this study, abdominal discomfort, bloating, frequency of bowel movements, and stool consistency were improved in patients treated with fluoxetine compared with placebo96.

As serotonin is a critical component in the regulation of gut motility, the systematic review found several studies that focused on targeting the serotonin receptor 5-HT₄ in the treatment of IBS-C. 5-HT₄ agonists evaluated for the treatment of IBS-C in the clinical studies identified included cisapride, tegaserod, and renzapride71,77,97–114. Tegaserod and renzapride demonstrated efficacy in providing relief of IBS symptoms71,111; however, both drugs have been associated with ischaemic colitis and tegaserod has been associated with a possible increased risk of serious cardiovascular events, which led to its withdrawal in 200771,115. Cisapride demonstrated no substantial benefit in IBS-C compared with placebo114 and was also withdrawn from the market following an association with rare dose-dependent cardiac events.

In addition, lubiprostone, a chloride channel activator, appeared to be effective in improving individual symptoms of IBS-C and was well tolerated64,69. Treatment with lubiprostone had no significant effect on patients’ quality-of-life (QoL), as evaluated by the IBS-QOL instrument64. Linaclotide, a minimally absorbed guanylate cyclase C agonist (GCCA), appeared to be well tolerated in patients with IBS-C, and was shown to improve bowel function and abdominal symptoms (including pain, bloating, and discomfort) and patients’ QoL70,116.

Discussion

This systematic review identified 106 studies reporting information on the burden of disease and unmet medical needs of patients with IBS-C. Most of these studies related to the diagnosis of IBS-C, its potential aetiology and clinical presentation, management guidelines, and treatment options, identifying a lack of published data relating to the burden of illness and economic burden of IBS-C from the European perspective. Indeed, economic studies in patients with IBS (not specifically IBS-C) were included in the review due to the dearth of European studies with IBS-C specific data.

The systematic review indicated a lack of studies evaluating the safety and efficacy of treatments prescribed for the symptoms of IBS-C (including laxatives, anti-spasmodics, and antidepressants) and the limited efficacy of current treatment options in alleviating the multiple symptoms of IBS-C. Therefore, there is a need for new therapies that are proven to be effective, well tolerated, and have a positive impact on HRQoL in patients with IBS-C. Indeed, several new treatment options for IBS-C are in development, including GCCAs and bile acid modulators; however, the GCCA, linaclotide, was the only drug currently in development for IBS-C that was identified by our systematic review70,116.

There is some discussion with regard to the validity and stability of the diagnosis of IBS-C117–119. In the absence of defined pathophysiology of aetiology for IBS, symptom-based diagnosis criteria for IBS have evolved over time, with refinements in descriptions and duration of symptoms, since the Manning criteria developed in 1978 to the latest Rome III diagnostic criteria31,37,39,51. Although there is evidence that patients can transition between different functional gastrointestinal disorders118, a symptom-based diagnosis of the IBS sub-types aids effective treatment and management of patients with this condition. IBS-C is a recognized sub-type of IBS, with distinguishable diagnostic criteria to functional constipation120. While there may be some symptom overlap between IBS-C and functional constipation or other IBS sub-types, to achieve positive outcomes for patients it is important that management approaches for IBS-C directly address the multiple overlapping symptoms of constipation, abdominal pain, discomfort, and bloating.

There is a lack of up-to-date treatment guidelines specific to the management of IBS-C. The systematic review found that the pharmacological and non-pharmacological treatment recommendations varied between guidelines, which may be due to the availability of evidence at the time of publication of each guideline. Indeed, the later guidelines make recommendations for pharmacological agents in IBS-C based on the emergence of new evidence, new agents, and clinical experience.

Symptom-based management may, therefore, often be based on clinical opinion, so there is a need to develop evidence-based clinical guidelines to provide clinicians with up-to-date recommendations for the treatment of patients with IBS-C.

Although no cost-of-illness studies for IBS-C in France, Germany, Italy, Spain, or the UK were identified by this systematic review, studies in patients with IBS provide evidence that IBS contributes to both direct and indirect healthcare costs and is a cost-intensive disease, possibly as it is chronic and non-fatal, with a relatively high prevalence in working-age adults. Two analyses of a clinical trial identified by our systematic review, assessing work productivity related to IBS-C treatment, suggested that effectively treating the symptoms of IBS-C can reduce presenteeism, absenteeism, and activity impairment15,77. Future research into the cost of illness for IBS and IBS-C is required to determine whether intensive consumption of healthcare resources is observed throughout Europe.

This systematic review did not identify any cost analyses for current IBS-C treatments from France, Germany, Italy, Spain, or the UK. However, a US model assessing the budgetary impact of tegaserod for IBS-C on a US managed-care organization (MCO) formulary, suggested that the use of tegaserod in women with IBS may be associated with reduced healthcare resource utilization121. The default 6-month cost of tegaserod was US$386.44 per patient (2003 costs) and the default MCO patient population was 10 million. The base-case model estimated an incremental per member per month budget impact of tegaserod use of US$0.01. For women with IBS, the calculated total cost per patient for the 6-month period was US$274.34, compared to US$301.84 for other GI diagnoses. In the IBS group, 29% of the cost of tegaserod was offset by reduced resource use; key drivers were fewer hospital stays (−US$38.61), outpatient office consultations (−US$18.20), and abdominal and pelvic computed tomography121.

In summary, our systematic review identified the need for more targeted research into IBS-C, to gain a better understanding of the specific disorder, treatment patterns, and the economic and humanistic burden to society, in order to address unmet patient needs.

Transparency

Declaration of funding

This study was sponsored by Almirall.

Declaration of financial relationships

Josep Fortea and Mercedes Prior are employees of Almirall. JME Peer Reviewers on this manuscript have no relevant financial relationships to disclose.

Acknowledgements

The authors would like to thank Ingela Wiklund, Talia Foster, and Karin Travers, who are employees of United Biosource Corporation, for their contribution to conducting this study. (Talia Foster was the Principal Investigator of the systematic literature search and Karin Travers was the Project Manager.) The authors would also like to thank Claire Chadwick, PhD, of Complete Clarity, who provided medical writing support funded by Almirall.