Systematic review: the safety and tolerability of pharmacological agents for treatment of irritable bowel syndrome--a European perspective

AIM: To use an evidence-based approach to evaluate the safety and tolerability of the treatments available for irritable bowel syndrome (IBS), or in clinical development, in Europe. A separate review appraises the evidence for the efficacy of these therapies. METHODS: A literature search (for 1980 to 2005) was completed for all relevant clinical trial data and other articles which included safety information on the use of pharmacological IBS therapies. Clinical trials were scored according to the level of safety information, and adverse event incidence reported when possible. RESULTS: The tolerability of many of the agents used to treat IBS in Europe is poorly understood. However, serotonergic agents, such as tegaserod and alosetron, which are currently unavailable in Europe, have undergone rigorous assessment in IBS and their benefits have been established. Following initial marketing of alosetron for use in patients with IBS with diarrhoea, concerns about severe constipation and ischaemic colitis resulted in restriction of its use to women with severe IBS symptoms. This highlights the importance of post-marketing surveillance and post-marketing studies in refining the therapeutic indication of new IBS therapies, which will help to identify appropriate recipients for the drug and establish the impact of adverse reactions in clinical practice. CONCLUSIONS: There is a significant lack of data on the safety and tolerability of the therapies currently used routinely to treat IBS in Europe. The newer agents have undergone rigorous assessment, such that their benefits and risks in treating IBS are established. Defining their place among the spectrum of available therapies remains challenging when the benefits and risks of the older treatments are so poorly characterized.     

Systematic review: the economic impact of irritable bowel syndrome

BACKGROUND: Although little mortality is associated with irritable bowel syndrome, curative therapy does not exist and thus the economic impact of this disorder may be considerable. METHODS: A systematic review of the literature was performed. Studies were included if their focus was irritable bowel syndrome, and direct and/or productivity (indirect) costs were reported. Two investigators abstracted the data independently. RESULTS: One hundred and seventy-four studies were retrieved by the search; 11 fulfilled all criteria for entry into the review. The mean direct costs of irritable bowel syndrome management were reported to be UK pound sterling90, Canadian$259 and US$619 per patient annually, with total annual direct costs related to irritable bowel syndrome of pound sterling45.6 million (UK) and $1.35 billion (USA). Direct resource consumption of all health care for irritable bowel syndrome patients ranged from US$742 to US$3166. Productivity costs ranged from US$335 to US$748, with total annual costs of $205 million estimated in the USA. Annual expenditure for all health care, in addition to expenditure limited to gastrointestinal disorders, was significantly higher in irritable bowel syndrome patients than in control populations. CONCLUSIONS: Despite the lack of significant mortality, irritable bowel syndrome is associated with high direct and productivity costs. Irritable bowel syndrome patients consume more gastrointestinal-related and more total health care resources than non-irritable bowel syndrome controls, and sustain significantly greater productivity losses.     

Systematic review: Complementary and alternative medicine in the irritable bowel syndrome

BACKGROUND: Complementary and alternative medical therapies and practices are widely employed in the treatment of the irritable bowel syndrome. AIM: To review the usage of complementary and alternative medicine in the irritable bowel syndrome, and to assess critically the basis and evidence for its use. METHODS: A systematic review of complementary and alternative medical therapies and practices in the irritable bowel syndrome was performed based on literature obtained through a Medline search. RESULTS: A wide variety of complementary and alternative medical practices and therapies are commonly employed by irritable bowel syndrome patients both in conjunction with and in lieu of conventional therapies. As many of these therapies have not been subjected to controlled clinical trials, some, at least, of their efficacy may reflect the high-placebo response rate that is characteristic of irritable bowel syndrome. Of those that have been subjected to clinical trials most have involved small poor quality studies. There is, however, evidence to support efficacy for hypnotherapy, some forms of herbal therapy and certain probiotics in irritable bowel syndrome. CONCLUSIONS: Doctors caring for irritable bowel syndrome patients need to recognize the near ubiquity of complementary and alternative medical use among this population and the basis for its use. All complementary and alternative medicine is not the same and some, such as hypnotherapy, forms of herbal therapy, specific diets and probiotics, may well have efficacy in irritable bowel syndrome. Above all, we need more science and more controlled studies; the absence of truly randomized placebo-controlled trials for many of these therapies has limited meaningful progress in this area.     

Systematic review: self‐management support interventions for irritable bowel syndrome

Aliment Pharmacol Ther 2010; 32: 513–521

Summary

Background Irritable bowel syndrome is an extremely common and costly condition. Because there is no cure, patients must be supported to manage their own condition. Aim To assess systematically the interventions used to support irritable bowel syndrome patient self‐management. Methods A search of PubMed, EMBASE, CINAHL and PsycINFO was performed to identify all studies that involved self‐management support interventions for irritable bowel syndrome. Studies that compared the self‐management‐related intervention to a control group were included. Results Eleven studies that involved a total of 1657 patients were included. For nearly all studies, the intervention was associated with statistically significant benefits. However, across studies there was significant heterogeneity in terms of sample size, diagnostic criteria, study setting, study design, primary outcome, statistical analyses and study quality. Therefore, individual study results could not be statistically combined. Conclusions Many self‐management support interventions appear benefit patients with irritable bowel syndrome. However, studies were limited by methodological flaws. Furthermore, feasibility in ‘real world’ clinical practice is uncertain. Thus, practical self‐management interventions that can be applied across various clinical settings should be developed, and then tested in well‐designed clinical trials.     

Systematic review: the influence of geography and ethnicity in irritable bowel syndrome

BACKGROUND: Irritable bowel syndrome has been said to be less common in developing countries compared with western populations. In some case series of irritable bowel syndrome from the Indian subcontinent and Africa, the female predominance typical of western patients did not occur. AIM AND METHODS: A systematic review was performed on Medline, of community prevalence studies of irritable bowel syndrome, chronic constipation and chronic diarrhoea using standardized criteria, with special reference to the effect of geography and ethnicity, and the gender distribution in different countries. RESULTS: There is a wide variation, depending in part on the criteria used and differences in diagnostic practices and health care utilization. No convincing evidence emerged of a difference between east and west. Most series, eastern or western showed a female predominance or no gender difference. Several US studies in communities and specific populations suggest that stool frequency is lower, and the prevalence of constipation higher, among Afro-Caribbean Americans compared with white individuals. CONCLUSIONS: Community studies in multi-racial populations are a useful way of assessing possible ethnic differences in the frequency of irritable bowel syndrome, chronic constipation and diarrhoea, and would additionally present opportunities to relate any ethnic differences to dietary and other environmental factors.     

Systematic review: the effectiveness of hypnotherapy in the management of irritable bowel syndrome

AIM: To systematically review the literature evaluating hypnotherapy in the management of irritable bowel syndrome (IBS). METHODS: Electronic databases were searched (Cochrane Library, Medline, CINAHL, AMED, Embase, PsycINFO, CISCOM, TRIP and the Social Science Citation index), bibliographic references scanned and main authors contacted. No restrictions were placed on language or publication year. Eligible studies involved adults with IBS using single-component hypnotherapy. All studies, except single case or expert opinion, were sought and all patient-related outcomes eligible. RESULTS: Out of 299 unique references identified, 20 studies (18 trials of which four were randomized, two controlled and 12 uncontrolled) and two case series were eligible. These tended to demonstrate hypnotherapy as being effective in the management of IBS. Numbers of patients included were small. Only one trial scored more than four out of eight on internal validity. CONCLUSION: The published evidence suggests that hypnotherapy is effective in the management of IBS. Over half of the trials (10 of 18) indicated a significant benefit. A randomized placebo-controlled trial of high internal validity is necessary to establish the effectiveness of hypnotherapy in the management of IBS. Until such a trial is undertaken, this form of treatment should be restricted to specialist centres caring for the more severe forms of the disorder.     

Comparison of various treatments for irritable bowel syndrome

A previous therapeutic trial of factorial design showed that a combination of a psychotropic drug, a smooth-muscle relaxant, and a bulk former (lorazepam, hyoscine hydrobromide, and ispaghula husk) relieved symptoms of the irritable bowel syndrome more effectively than the same agents given singly. Another trial of similar design was undertaken to compare each of these three agents with another having the equivalent clinical actions--namely, Motival (fluphenazine/nortriptylene mixture), mebeverine, and bran. Ninety-six patients took part; all received three agents, one from each of the three pairs being compared, and no placebos were used. Fifty-six patients reported a sustained symptomatic improvement, which was a significantly higher incidence than in the previous trial, when placebos were used. Ispaghula was significantly more effective than bran. The combination of ispaghula, Motival, and mebeverine improved 11 out of 12 patients--significantly more than bran, Motival, and hyoscine (five improved), or bran, lorazepam, and mebeverine (four improved). Mebeverine was significantly more effective when combined with Motival (18 out of 24 improved) than with lorazepam (10 improved). These results confirm the value of a combined therapeutic approach to the relief of the irritable bowel syndrome and suggest the possibility of synergism between agents.     

Systematic review: Abdominal and pelvic surgery in patients with irritable bowel syndrome

AIM: To systematically review research on the prevalence of abdominal and pelvic surgery in patients with irritable bowel syndrome. METHODS: Computer searches of MEDLINE, EMBASE and Current Contents were performed independently by both investigators to identify appropriate studies. Primary study selection criteria included: (i) population-based samples of adult irritable bowel syndrome patients; (ii) the use of appropriate symptom-based criteria to identify irritable bowel syndrome patients; and (iii) comparison of the prevalence of abdominal and pelvic surgery in irritable bowel syndrome patients vs. control populations. Secondary analysis was performed on published studies of referral populations and case series. RESULTS: Two population-based studies met the primary study selection criteria and revealed an increased prevalence of surgery in irritable bowel syndrome patients vs. controls for cholecystectomy (4.6% vs. 2.4%, respectively; odds ratio, 1.9; 95% confidence interval, 1.2-3.2) and hysterectomy (18% vs. 12%, respectively; odds ratio, 1.6; 95% confidence interval, 1.1-2.2). Secondary analysis revealed an increased prevalence of appendectomy and other abdominal and pelvic surgery in irritable bowel syndrome patients. CONCLUSIONS: Irritable bowel syndrome is associated with a disproportionately high prevalence of abdominal and pelvic surgery, but most studies exhibit sub-optimal study design and do not define the factors causing the increased prevalence of surgery in these patients.     

Systematic review: accuracy of symptom-based criteria for diagnosis of irritable bowel syndrome in primary care

Background  Despite the trend towards making a positive diagnosis of irritable bowel syndrome (IBS), many health care providers approach IBS as a diagnosis of exclusion.
Aim  To summarize available evidence on the diagnostic performance of symptom-based IBS criteria in excluding organic diseases, and of individual signs and symptoms in diagnosing IBS and to additionally assess the influence of sources of heterogeneity on diagnostic performance.
Methods  We searched PubMed and EMBASE and screened references. Studies were selected if the design was a primary diagnostic study; the patients were adults consulting because of non-acute abdominal symptoms; the diagnostic test included an externally validated set of IBS criteria, signs, or symptoms. Data extraction and quality assessment were performed by two reviewers independently. The review adhered to the most recent guidelines as described in the Cochrane Diagnostic Reviewers' Handbook.
Results  A total of 25 primary diagnostic studies were included in the review. The performance of symptom-based criteria in the exclusion of organic disease was highly variable. Patients fulfilling IBS criteria had, however, a lower risk of organic diseases than those not fulfilling the criteria.
Conclusions  With none of the criteria showing sufficiently homogeneous and favourable results, organic disease cannot be accurately excluded by symptom-based IBS criteria alone. However, the low pre-test probability of organic disease especially among patients who meet symptom-based criteria in primary care argues against exhaustive diagnostic evaluation. We advise validation of the new Rome III criteria in primary care populations.     

Systematic review and meta-analysis: The incidence and prognosis of post-infectious irritable bowel syndrome

BACKGROUND: Individual studies suggest that post-infectious irritable bowel syndrome is common, but symptoms gradually improve. AIM: To review evidence for an association between intestinal infection and development of irritable bowel syndrome, assess the prognosis of post-infectious irritable bowel syndrome and explore factors that increase the risk. METHODS: MEDLINE (1966-2007) and EMBASE (1980-2007) databases were searched to identify the studies of post-infectious irritable bowel syndrome epidemiology. Data were extracted by two independent reviewers. Pooled odds ratios (POR) and corresponding 95% CI for incidence of irritable bowel syndrome were estimated among the exposed and unexposed groups. RESULTS: Eighteen of 26 studies identified were eligible for inclusion. Intestinal infection was associated with increased odds of developing irritable bowel syndrome at study end (POR = 5.86; 95% CI: 3.60-9.54). In subgroup analysis, the odds of developing irritable bowel syndrome was increased at 3 months (POR = 7.58; 95% CI: 4.27-13.45), 6 months (POR = 5.18; 95% CI: 3.24-8.26), 12 months (POR = 6.37; 95% CI: 2.63-15.40) and 24-36 months (POR = 3.85; 95% CI: 2.95-5.02). Among all studies (controlled and uncontrolled), the pooled incidence of irritable bowel syndrome at study conclusion was 10% (95% CI: 9.4-85.6). Subjects with post-infectious irritable bowel syndrome were younger and more anxious and depressed than those without post-infectious irritable bowel syndrome. CONCLUSION: The odds of developing irritable bowel syndrome are increased sixfold after acute gastrointestinal infection. Young age, prolonged fever, anxiety and depression are risk factors for post-infectious irritable bowel syndrome.     

Naloxone treatment for irritable bowel syndrome--a randomized controlled trial with an oral formulation

BACKGROUND: Opioids change gut motility and secretion, causing delayed intestinal transit and constipation. Endorphins play a role in the constipation troubling some patients with irritable bowel syndrome; hence naloxone, an opioid antagonist, may have a therapeutic role. AIM: To assess the efficacy and safety of an oral formulation of naloxone in irritable bowel syndrome patients with constipation. METHODS: A randomized, double-blind, placebo-controlled trial was performed. Patients fulfilling the Rome II criteria for irritable bowel syndrome (constipation-predominant and alternating types) were randomized to receive 8 weeks of treatment with naloxone capsules, 10 mg twice daily, or identical placebo. RESULTS: Twenty-eight patients entered the study, which was completed by 25. 'Adequate symptomatic relief' was recorded in six of 14 on naloxone and three of 11 on placebo. Whilst the differences were not significant, improvements in severity gradings and mean symptom scores for pain, bloating, straining and urgency to defecate were greater with naloxone than placebo for all parameters. In addition, quality of life assessments improved to a greater extent in patients taking naloxone. CONCLUSIONS: Preliminary results suggest that naloxone is well tolerated and beneficial in patients with irritable bowel syndrome and constipation. A larger clinical trial is needed to provide sufficient statistical power to assess efficacy.     

Clinical economics review: irritable bowel syndrome

The ubiquitous nature of irritable bowel syndrome (IBS), coupled with a lack of good treatment options, has created the impression that the condition must represent a large drain on health-care resources. The literature certainly appears to support this view but is largely based on patients seen in referral centres (10–15%) and it may not be appropriate to extrapolate these data to the IBS population as a whole (85–90%).
In addition to reviewing such literature that exists on the economics of IBS, this paper contains some new data, which suggest that the direct costs of the condition, certainly in the UK, may not be quite as high as has previously been assumed. This may be partly due to factors such as the low cost of the drugs used to treat the condition and the tendency for many patients to stop consulting because of disenchantment with the inadequacies of current therapy. Conversely, the indirect and intangible costs of the disorder appear to be much greater, but these burdens obviously do not have such an impact on those responsible for purchasing and providing health care for IBS sufferers.
Paradoxically, if a new, effective therapy for IBS were forthcoming, the situation could change dramatically, especially if it involved a new drug. Any such agent would inevitably be more expensive than anything available today, leading to a potentially dramatic escalation in the direct costs of this disorder.     

A review of the clinical efficacy of linaclotide in irritable bowel syndrome with constipation

Abstract

Objectives:

The aims were: firstly, to review the definition and diagnosis of irritable bowel syndrome with constipation (IBS-C, a subtype of IBS); secondly, to critically assess current therapies for IBS-C with a focus on effectiveness for abdominal pain; and thirdly, to review clinical studies evaluating the efficacy of linaclotide, a therapy recently approved by the US Food and Drug Administration for the treatment of adults with IBS-C and chronic idiopathic constipation and the European Medicines Agency for the symptomatic treatment of moderate to severe IBS-C in adults, and in development for treatment of IBS-C worldwide.