Optimizing treatment for patients with irritable bowel syndrome with constipation

Irritable bowel syndrome (IBS) has finally reached the category of established illness, and gained both social recognition and acceptability. Nowadays, both patients and physicians feel comfortable with an IBS diagnosis as a solid basis for a therapeutic plan. It has been a long and eventful journey. As Stanghellini points out in his thoughtful review of the evolution of the IBS concept [1], it began as an exclusion diagnosis. Therefore, patients with various types of abdominal pain, disturbed bowel pattern and other abdominal symptoms were considered to suffer from IBS only after exhaustive, and often repeated, work-up that indicated significant lesion or disease was not present. This approach to IBS diagnosis almost inevitably left patients and their physicians with the nagging feeling that something important may have been missed, which perhaps could be identified by further diagnostic evaluation. Today we view IBS as a biopsychosocial disorder in which a number of established pathophysiological factors act together to a variable extent to create an individualized but recognizable clinical picture. Hence, we strive to make a positive diagnosis of IBS by applying validated symptom criteria and pointedly restricting investigations to a minimum, triggered by specific alarm features. Positive diagnosis of IBS results in significant economic savings by avoiding unnecessarily extensive diagnostic tests and better acceptance by patients that a firm diagnosis has been reached.

Unfortunately, elation with diagnostic success often evolves into frustration owing to unsatisfactory treatment. In his article, Layer outlines in detail the current therapeutic arsenal comprising behavioral modification, diet, pharmacological agents and other instruments at our disposal to help relieve IBS symptoms and improve the patient’s quality of life [2]. It is a somewhat depressing list (even though antidepressants are part of it!), for effectiveness is meagre. Furthermore, some of the approaches carry relatively common and substantial side effects. In addition, let’s be clear, our patients demand symptom relief, not symptom replacement!

Among the therapeutic measures currently proposed for IBS, dietary modification is gaining popularity, including gluten-free or FODMAP (fermentable oligo-, di- and mono-saccharides, and polyols; a collection of short-chain carbohydrates found in many common foods) diets. Regardless of the actual improvement obtained by adhering to such strict diets, consideration must be given to the inconvenience and expense of adapting one’s lifestyle to dietary compliance. Again, for a condition such as IBS that primarily affects quality of life, added personal burdens do not seem an ideal therapeutic solution except, perhaps, for a minority of highly motivated patients.

Furthermore, current management of IBS often entails combining a number of measures to achieve some degree of patient satisfaction. The problem is particularly blatant for IBS with constipation (IBS-C). In this highly prevalent subgroup of IBS, laxatives are often prescribed to relieve constipation in association with antispasmodic or other pain-relieving agents. Even if the combined approach is successful, other symptoms remain, such as bloating. Therefore, there is demand for a single, effective drug that would provide global symptom relief and elicit a high level of satisfaction for patients and their physicians.

Linaclotide, a new agent, is an ingeniously designed and remarkable drug. As a minimally absorbed guanylate cyclase C agonist, it stimulates cyclic guanosine monophosphate release by the enterocytes. Cyclic guanosine monophosphate activates a molecular pathway that increases intestinal secretion into the lumen and simultaneously reduces pain sensitivity through its antinociceptive effects on subepithelial intestinal pain fibers. In his article, Blackshaw clearly and elegantly explains the mechanisms by which linaclotide may inhibit intestinal sensory nerves and provides a plausible and highly fundamental model for the pain-relieving effects of this agent in IBS-C [3]. These pain-relieving effects appear to go somewhat beyond what would be expected by unloading of retained stool. Tack, in his contribution to the supplement, brings all this new information together and details the scientific evidence accrediting the clinical effectiveness of linaclotide in IBS-C [4]. Indeed, several large and well-designed clinical trials validate the clinical usefulness of linaclotide. Statistical analysis has demonstrated that linaclotide is able to substantially increase bowel movements as soon as patients start treatment, and led to US FDA approval for treatment of IBS-C in the USA; linaclotide has now also been licensed by the EMA for the treatment of IBS-C in Europe [101]. Furthermore, analysis showed that improved defecation frequency and completeness of bowel movements are sustained by at least 26 weeks of continuous medication. At the same time, abdominal pain and discomfort are ameliorated, albeit more gradually, reaching maximum improvement by 4 weeks and plateauing afterwards for up to 26 weeks. Improvement in bloating follows a similar pattern. Patient satisfaction and improved quality of life occur in concert with symptom relief. Linaclotide appears to be a remarkably well-tolerated drug. Mild-to-moderate diarrhea (a not-so-unwelcome effect in constipated individuals) is the only substantial side effect detected in the trials.

I believe you will find this series of articles informative and appealing. They convey a message of hope for successful management of IBS-C. From a disregarded and poorly defined collection of symptoms, IBS has fortunately evolved into a well-established entity with positive diagnostic criteria. Effective treatment has lagged somewhat behind, but now, at least for IBS-C, there is a new agent that genuinely offers the possibility to many patients of obtaining sustained remission of their symptoms and a chance to return to an unworried and healthy digestive life.

Financial & competing interests disclosure

J-R Malagelada received financial compensation for his position on advisory boards and as a Consultant from Almirall and Shire, and received a research grant from Given. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Editing support for English language was provided by Complete Medical Communications Ltd and was funded by Almirall.