Irritable Bowel Syndrome: Recent Trends in Management

Introduction

Irritable bowel syndrome (IBS) is a disorder that can be diagnosed positively on the basis of symptom criteria and evaluation to exclude organic diseases.¹Camilleri M, Heading R C & Thompson W G. Consensus report: clinical perspectives, mechanisms, diagnosis and management of irritable bowel syndrome. Aliment Pharmacol Ther. 2002; 16: 1407-1430.   Irritable bowel syndrome is among the most commonly encountered chronic functional gastrointestinal (GI) disorders afflicting individuals. Based on the Rome-III criteria abdominal pain accompanied by sustained changes in bowel habit constitute IBS, whose diagnosis is achieved in the absence of biochemical markers of disease. Clinical presentation of constipation, diarrhoea or a combination, constitutes the different subtypes of IBS: IBS with Constipation (IBS-C), IBS with Diarrhoea (IBS-D), Mixed IBS (IBS-M), Post infectious IBS (Pi-IBS), respectively.²Beatty K J, Bhargava A, Buret A G. Post-infectious irritable bowel syndrome: Mechanistic insights into chronic disturbances following enteric infection. World J Gastroenterol. 2014 April; 20(14): 3976-985.  

Burden of Disease

The Indian Society of Gastroenterology-led Task Forces have recently published that the pan-Indian prevalence of irritable bowel syndrome is 4.2% (4 crores Indians suffer from IBS). World Gastroenterology Organisation (WGO) has given ten general dietary tips for healthy gut. Two of these dietary tips i.e., use of probiotics/fermented food and a high fiber diet, are followed by most Indians.³Bhatia SJ, Reddy DN, Ghoshal UC, et al Epidemiology and symptom profile of gastroesophageal reflux in the Indian population: report of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol. 2011; 30: 118-27.  ⁴Ghoshal UC, Abraham P, Bhatt C, Choudhuri G, Bhatia SJ, Shenoy KT, et al. Epidemiological and clinical profile of irritable bowel syndrome in India: report of the Indian Society of Gastroenterology Task Force. Indian J Gastroenterol. 2008; 27: 22-8.   Although IBS affects both sexes, 60% to 75% of sufferers are women.⁵Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002; 122: 1140-56.   ⁶Mayer EA, Naliboff B, Lee O, et al. Review article: gender related differences in functional gastrointestinal disorders. Aliment Pharmacol Ther.1999; 13(suppl 2):65-69.   Younger patients are more likely to be affected by IBS than are the elderly .⁷Brandt LJ, Bjorkman D, Fennerty MB, et al. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol. 2002; 97: S7-S26.   Patients with IBS symptoms typically present to a physician for the first time between the age of 30 and 50 years.⁸Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002; 123: 2108-31.   The prevalence of IBS diminishes in patients older than 60 years.⁹ Irritable bowel syndrome in women: the unmet needs. Washington, DC:Society for Women’s Health Research; 2002:1-37.  

Post infectious IBS cases often exhibit characteristics of the IBS-D and can occur in 4%-31% of patients following acute gastroenteritis. A large body of work provides evidence supporting a role for pathogen-mediated modifications in the resident intestinal microbiota, epithelial barrier integrity, enterochromaffin cell function and innate immune features in Pi-IBS manifestation. Any number of these pathogenic consequences have been reported following enteric infection incited by an array of pathogens such as Shigella spp., pathogenic Escherichia coli, Salmonella, Campylobacter jejuni and Giardia duodenalis.²Beatty K J, Bhargava A, Buret A G. Post-infectious irritable bowel syndrome: Mechanistic insights into chronic disturbances following enteric infection. World J Gastroenterol. 2014 April; 20(14): 3976-985.  

Pathogenesis

To date, no physiologic mechanism unique to IBS has been identified. Considered initially as the consequence of abnormal gut motility, visceral hypersensitivity, psychosocial factors and brain-gut axis dysfunction, IBS is now acknowledged as a multifactorial disorder. Specific peripheral mechanisms are involved, including abnormal colonic transit and rectal evacuation; intraluminal intestinal irritants, such as maldigested carbohydrates (producing short chain fatty acids) or fats, an excess of bile acids, and gluten intolerance; alterations in the microbiome; entero-endocrine-cell products; and genetic susceptibility to inflammation or altered bile acid synthesis. These luminal and mucosal irritants alter mucosal permeability and cause immune activation or inflammation, which in turn activates local reflexes that alter intestinal motility or secretion. The irritants also stimulate sensory mechanisms, leading to visceral hypersensitivity and pain. A greater understanding of these mechanisms may foster individualized, specific treatments for patients with IBS¹⁰Camilleri M. Peripheral mechanisms in irritable bowel syndrome. N Engl J Med 2012;367:1626-35.  

Proposed Integrative Model: “Integrative Multiple Hits Model”¹¹Mayer EA, Naliboff BD, Chang L, Coutinho SV. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2001; 280(4): G519-G524.  

Given the diversity of pathophysiological mechanisms known currently, it is essential to develop a disease model integrating the multifactorial aspects of disease-related differences in IBS. Such a model could be helpful to identify research avenues leading to a better understanding of IBS aetiology. An “Integrative Multiple Hits Model” can thus be proposed to account for the numerous IBS risk factors, their possible interplay and their time scale in the course of IBS development (Figure 1).

Abnormal Gut Motility

The changes in gut motility observed in IBS are qualitative, with no distinct pattern that can distinguish patients from healthy subjects. Numerous motility abnormalities that affect the GI tract have been identified in patients who have IBS. For example, patients who have a predominant symptom of diarrhoea seem to have accelerated whole gut and colonic transit times. Conversely, patients who have constipation-predominant IBS demonstrate decreased migrating motor complexes compared with controls who did not have IBS.

Psychosocial Factors

IBS has long been dismissed as a psychosomatic condition because it has no clear cause or pathophysiology. Psychological stress and emotional events, such as physical or sexual abuse, can result in GI symptoms in healthy subjects, but they affect patients with IBS to a greater degree. The common psychological symptoms associated with IBS are depression, somatisation, anxiety, hostility, phobia and paranoia. Up to 50% of patients with IBS meet criteria for a psychiatric diagnosis as compared with an average of 20% with organic GI disorders and 15% of control subjects.⁸Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel syndrome. Gastroenterology. 2002; 123: 2108-31.   Although there are no psychological or psychiatric disorders specific to IBS, identification of such disorders can help in planning psychological or psychopharmacologic treatment.

Visceral Hypersensitivity and Brain-gut Interactions

Pain is a central requirement of the definition and diagnosis of IBS. Over the past 20 years, the potential roles of heightened visceral sensation, also referred to as ”visceral hypersensitivity” and abnormalities in brain gut interactions has been implicated in the pathogenesis of IBS. Several investigators have reported a heightened visceral sensation in response to rectal distention in patients who had IBS and other functional GI disorders. In addition, recent work using positron emission tomography scanning and functional MRI identified abnormalities in brain activation in patients who had IBS as compared to controls. Abnormalities have been identified consistently in the activation of the anterior cingulate cortex which likely plays an important role in the development of attention to a painful stimulus, the unpleasantness associated with a painful stimulus and the attribution of an emotional response to a painful stimulus. The anterior cingulate cortex also plays an important role in the activation of descending inhibitory pathways that help to gate or control the passage of afferent information from the periphery to the brain. The understanding of the enteric nervous system and the role that abnormalities in the enteric nervous system may play in patients who have IBS continues to evolve. The enteric nervous system functions semi-autonomously but can be modulated by input from the autonomic nervous system. In this way, the enteric nervous system plays a critical role in modulation of GI motility addition, recent work using positron emission tomography scanning and functional MRI identified abnormalities in brain activation in patients who had IBS as compared to controls. Abnormalities have been identified consistently in the activation of the anterior cingulate cortex which likely plays an important role in the development of attention to a painful stimulus, the unpleasantness associated with a painful stimulus and the attribution of an emotional response to a painful stimulus. The anterior cingulate cortex also plays an important role in the activation of descending inhibitory pathways that help to gate or control the passage of afferent information from the periphery to the brain. The understanding of the enteric nervous system and the role that abnormalities in the enteric nervous system may play in patients who have IBS continues to evolve. The enteric nervous system functions semi-autonomously but can be modulated by input from the autonomic nervous system. In this way, the enteric nervous system plays a critical role in modulation of GI motility and secretory function. Evolving evidence has implicated several neuromodulators, including serotonin, in the normal function of the enteric nervous system.¹²Cash B D, Chey W D. Irritable bowel syndrome: A systemic review. Clinics in family practice. 2004 Sept., Volume 6, Number 3.  

Latent or Potential Celiac Disease

The concept of latent or potential celiac disease has recently been introduced into the pathogenesis of IBS. Abdominal symptoms in the absence of mucosal abnormalities are features of IBS and latent or potential celiac disease.¹³Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology. 2001, 121: 1329-1339.   In a study of genetic, serologic, and histologic markers of celiac disease in 102 patients with diarrhoea-predominant IBS, 35% of the patients had positive findings for human leukocyte antigen (HLA)-DQ2, 23% had increased intraepithelial lymphocyte counts and 30% had increased celiac disease-associated antibodies in the duodenal aspirates, including antibodies against gliadin, tissue transglutaminase, β-lactoglobulin and ovalbumin.¹³Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology. 2001, 121: 1329-1339.   Stool frequency and the intestinal immunoglobulin A (IgA) level decreased significantly under a gluten-free diet in a subgroup of IBS patients with positive HLA-DQ2 and positive intestinal celiac disease-associated antibodies when compared with IBS patients without these markers.¹³Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology. 2001, 121: 1329-1339.   Celiac disease-associated IgG and HLADQ2 expression can identify likely responders to gluten-free diet in patients with IBS-D (diarrhoea predominant IBS).¹⁴Wahnschaffe U, Schulzke J, et al: Predictors of clinical response to gluten-free diet in patients diagnosed with diarrhea-predominant irritable bowel syndrome. ClinGastroenterolHepatol. 2007; 7: 844-50.  

Infection and Inflammation

Clinical, epidemiologic and physiologic studies have shown that acute, transient GI infection is associated with a syndrome that often meets diagnostic criteria for the diagnosis of IBS. This was observed after documented outbreaks of enteric infections with organisms such as Campylobacter jejuni or Salmonella.¹⁵Spiller RC, Jenkins D, Thornley JP, et al: Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000; 47: 804-11.   ¹⁶Mearin F, Pérez-Oliveras M, Perelló A, et al: Dyspepsia and irritable bowel syndrome after a Salmonella gastroenteritis: One-year follow-up cohort study. Gastroenterology. 2005, 129: 98-104.   IBS and small intestine bacterial overgrowth (SIBO) might share similar symptoms. In a study of 202 patients with IBS, 157 (78%) patents had SIBO. Intraepithelial lymphocytes, lamina propria CD3 and CD25 cells, neutrophils, and mast cells were increased in patients with IBS.¹⁷Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000, 95: 3503-06.  

The exact mechanisms whereby the inflammatory changes cause the symptoms are not clear. The inflammatory response may be associated with activating enterochromaffin cells to produce 5-hydroxytryptamine (5-HT) and CD3 cells to produce cytokines, which in turn leads to enhanced motility, increased intestinal permeability and lowered visceral sensation thresholds.¹⁸Collins SM, Vallance B, Barbara G, Borgaonkar M. Putative inflammatory and immunological mechanisms in functional bowel disorders. Baillieres Best Pract Res Clin Gastroenterol. 1999, 13: 429-36.  

Clinical Presentations of IBS

Patients with IBS can present with a wide variety of GI and extraintestinal symptoms. However, the symptom complex of chronic abdominal pain and altered bowel habits that cannot be explained by identifiable structural or biochemical abnormalities is the main clinical pattern of IBS. Chronic abdominal pain in IBS is usually described as a crampy sensation, with varying intensity and periodic exacerbation. The pain is generally located in the lower abdomen, although the location and character of the pain can also vary. Emotional stress and eating can exacerbate the pain, whereas defecation often provides some relief. Because the range of normal bowel habits is broad, a careful history should include the volume, frequency and consistency of the patient’s stool. The frequency of bowel movements in normal persons is variable and it can range from three times a day to three times a week. Patients with IBS complain of diarrhoea, constipation, alternating diarrhoea and constipation or normal bowel habits alternating with diarrhoea or constipation reflecting intestinal transit time.¹⁹Longstreth G, Thompson W, Chey WD, et al. Functional bowel disorders. Gastroenterology. 2006, 130: 1480-91.  

Other Gastrointestinal Symptoms

Upper GI symptoms are not uncommon in patients with IBS. These include symptoms of heartburn, dysphagia, nonulcer dyspepsia, nausea and noncardiac chest pain.²⁰Lynn RB, Friedman LS.Irritable bowel syndrome. N Engl J Med. 1993, 329:1940-45.   Patients with IBS often complain of abdominal bloating and increased gas production in the form of flatulence or belching.

Extraintestinal Symptoms

Patients with IBS have a high frequency of non-GI symptoms, including rheumatologic symptoms, headache, genitourinary symptoms such as urinary frequency and urgency, dyspareunia, sexual dysfunction and sleep-related disturbances.⁵Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology. 2002; 122: 1140-56.  

Diagnostic Investigations

A meticulous history is the key to establish a diagnosis of IBS. The Rome III criteria provide the basis upon which questions are based. Physicians should be guided by diagnostic criteria rather than approaching IBS as a diagnosis of exclusion.

A careful history taking, general examination and looking for alarm features (weight loss, rectal bleeding, nocturnal symptoms, anaemia, family history of colorectal cancer, IBD) can help make the diagnosis. Patients suspected to have organic disease should undergo further evaluation as indicated. Specific biomarkers for IBS do not exist. Current recommendations (Table 1) suggest sending complete blood count (CBC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) initially. In India, stool should be sent for routine microscopic examination. Routine thyroid function test (TFT), colonoscopy and diagnostic imaging are not advised unless there are alarm features.

IBS Diagnostic Criteria

A diagnosis is based on identifying positive symptoms consistent with IBS and excluding other conditions with similar clinical presentations in a cost-effective manner. In the absence of biologic markers, attempts have been made to standardise the diagnosis of IBS using symptom-based criteria. These include criteria proposed by Manning and colleagues in 1978²¹Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. Br Med J. 1978; 2: 653-54.   and the international workshop criteria, Rome I and II, with the updated current Rome III criteria. In the criteria of Manning and associates, the symptoms associated with IBS included relief of pain with bowel movements, looser and more frequent stools with onset of pain, passage of mucous and a sense of incomplete evacuation. The current Rome III criteria (Table 2 ) are a simplification of the Rome II criteria.

Treatment Protocol of IBS²²Mertz HR. Irritable bowel syndrome. N Engl J Med. 2003; 349: 2142.  

There is no single consistently successful therapeutic approach for patients who have IBS. Because IBS typically is a chronic condition, the goals of therapy should focus on patient reassurance, education about the syndrome and symptom improvement, rather than on disease cure. This is best achieved through a welldeveloped patient-physician relationship with a clear delineation of realistic goals and expectations. Most patients with have IBS (i.e., those who have mild symptoms and minimal impairment) can be managed at the primary care level. Fewer than 25% of patients who have IBS have more severe symptoms with significant lifestyle impairment and require management by a gastroenterologist. Finally, approximately 5% of patients who have IBS have such severe and incapacitating symptoms that they require referral to a center with multispecialty capability.

Pharmacologic Therapies

In 2002, a systematic review and clinical practice guideline for the management of IBS was published by the American College of Gastroenterology (ACG). This document largely conformed to evidence-based medicine criteria for a systemic review and critically assessed and graded the various treatment approaches for IBS. According to this document, traditional therapies, including bulking agents, antidiarrhoeals, antispasmodics and behavioral therapy, were believed to be effective for individual IBS symptoms.

Role of Diet

Patients with IBS commonly complain that specific dietary misadventures contribute to their symptoms of abdominal discomfort, bloating, or exaggerated gastro-colic reflex (urgent bowel movement after eating a meal). The truth is that no specific food is likely the culprit because true food allergies are rare. It is merely the act of eating that most likely initiates these postprandial symptoms. Patients may begin to associate ingestion of certain foods such as fatty foods, caffeine, alcoholic beverages, carbonated foods, or gas-producing foods as the aetiology of their complaints. The physician does not want to restrict the patients’ diet excessively because of the risk of encountering nutritional deficiencies. However, it may be a good idea to instruct the patient to limit suspected foods and slowly reintroduce these items individually to see if similar symptoms reoccur. The patient can record their food encounters and subsequent symptoms with a food diary. Maintaining a daily food diary can empower patients by allowing them to take an active role in their management. Cash et al demonstrated that lactose intolerance, one of the most commonly occurring disorder worldwide, was equally prevalent among IBS patients and the general population. Symptoms may be related to impaired absorption of carbohydrates in some patients. Specifically, one can target the fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs). This group includes fructans, galactans, lactose, fructose, sorbitol, xylitol, and mannitol. Fifteen studies are documenting improvement in patients who restrict their diets of these foods; nonetheless, this is a safe option to consider.²³Occhipinti K, Smith J W. Irritable Bowel Syndrome: A Review and Update. Clin Colon Rectal Surg. 2012; 25:46-52.  

Role of Fibre

Increased dietary fibre or psyllium products are frequently recommended for irritable bowel syndrome patients with constipation, even though, as a group, these patients do not consume less dietary fibre than control subjects. There is evidence that fibre decreases the whole-gut transit time, which may alleviate constipation. Fibre may also decrease intra-colonic pressures, either by a direct effect or by binding bile salts, and this could reduce pain as wall tension contributes to visceral pain. However, in one study, fibre supplementation did not reduce phasic contractile activity in a group of irritable bowel syndrome patients, and its effects on colonic tone, sensation and compliance have not been satisfactorily evaluated. Clinically, bran is reported to be no better than placebo in the relief of the overall symptoms of irritable bowel syndrome, and may possibly be worse than a normal diet for some symptoms of irritable bowel syndrome.

Two factors may play a role in the aggravation of irritable bowel syndrome symptoms, namely short chain fatty acids and gas. Short-chain fatty acids are the result of bacterial fermentation of dietary fibre, producing gas. Short-chain fatty acids may reduce thresholds of sensation, stimulate rectal contractions and provoke pain in irritable bowel syndrome patients. Preliminary data suggest that, while fibre accelerates small bowel transit in healthy subjects, it has no effect on small bowel and proximal colonic emptying. Furthermore, fibre increased residue loading and bacterial fermentation without facilitating colonic clearance.

In practice, many irritable bowel syndrome patients complain of bloating with higher doses of natural fibre. However, there is a significant improvement in constipation if sufficient quantities of fibre or nonabsorbed carbohydrate (20-30 g/day) are consumed. Synthetic ‘fibre’, such as polyethylene glycol or calcium polycarbophil, which cannot be split by bacteria, may be better tolerated than natural fibre. Thus, whereas fibre has a role in treating constipation, its value for irritable bowel syndrome, pain and diarrhoea is controversial.¹Camilleri M, Heading R C & Thompson W G. Consensus report: clinical perspectives, mechanisms, diagnosis and management of irritable bowel syndrome. Aliment Pharmacol Ther. 2002; 16: 1407-1430.  

Probiotics

The human gastrointestinal tract is a complex system containing a variety of bacterial communities of microflora. Probiotics are defined as “live, micro-organisms, which when consumed in adequate amounts, confer a health effect on the host.” A variety of probiotic strains are found in the gut and many strains are available commercially. The most common probiotic products contain Lactobacillus, Bifidobacterium, Enterococcus, streptococcus and Leuconostoc strains. Many clinical trials have been conducted regarding the role of probiotic therapy in a variety of disease states. In recent years, probiotics have gained attention for the treatment of IBS. Some studies suggest that patients who use probiotics to help alleviate IBS find modest improvement in overall symptoms after several weeks of treatment. Although many studies have been conducted in this area, the heterogeneity of study designs makes comparisons difficult.²⁴Spiller R. Review article: probiotics and prebiotics in irritable bowel syndrome. Aliment Pharmacol Ther. 28, 385-96.   ²⁵Hosseini A, Nikfar S, Abdollahi M. Are probiotics effective in management of irritable bowel syndrome? Arch Med Sci 3. 2012, June; 8, 3: 403-05.  

Antidiarrhoeal Agents

Within this class of compounds, the agent that has been most extensively evaluated is the synthetic opioid, loperamide. Loperamide (2-4 mg, up to four times daily) retards intestinal transit, enhances intestinal water and ion absorption and increases anal sphincter tone at rest. These physiological actions seem to explain the improvement in diarrhoea, urgency and faecal soiling observed in patients with irritable bowel syndrome. Other symptoms, such as pain and bloating, are not improved by loperamide. The effect on resting anal tone may help reduce faecal soiling at night-time if the internal anal sphincter is weakened. Because it does not traverse the blood-brain barrier, loperamide is generally preferred to other opiates, such as diphenoxylate or codeine. Clinical experience suggests that loperamide can also reduce urgency associated with feeding, anticipated stress or other colonic stimuli, such as exercise, social gatherings, etc. Formal studies are not available. The effects of loperamide on pain in irritable bowel syndrome are unclear and there are no long-term efficacy or safety data for loperamide. Cholestyramine is a second-line treatment for diarrhoea in irritable bowel syndrome, if bile acid is suspected.²⁶Ruepert L, Quartero AO, de wit NJ, et al. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database SystRev2011 (8) . Arti clenumber : CD003460 . DOI:10:1002/14651858 CD003460.pub3.  

Antispasmodics

Irritable bowel syndrome patients have altered visceral nociception or perception of gastro-intestinal stimuli. They are very sensitive to any pressure or pain in the GI tract. The increased sensitivity can be so pronounced that even normal intestinal contractions or gas can cause discomfort or pain. Increased sensitivity to pain is referred to as visceral hypersensitivity or hyperalgesia. Irritable bowel syndrome is characterised by persistent or recurrent abdominal, pelvic or back pain, abdominal distension and abnormal bowel movements. Some individuals suffer from diarrhoea and constipation. Others have prolonged constipation followed by a bout of diarrhoea. The passage of mucus in the stools is common, as is a sensation of incomplete evacuation. Diarrhoea is usually worse in the morning and after meals. Managing abdominal pain in IBS has changed very little over the past few decades: antispasmodics remain a cornerstone of therapy. Some agents like dicyclomine and hyoscyamine have antispasmodic properties but these drugs also have anticholinergic side effects. These anticholinergic side effects worsen gastroesophageal reflux disease. The anticholinergic side effects, including constipation, dry mouth, visual disturbances and urinary retention, can lead to discontinuation of these medications.

Mebeverine is a musculotropic spasmolytic with a strong and selective action on the smooth muscle spasm of the gastrointestinal tract, particularly of the colon. But it takes about two hours to act and is not reported to provide Global improvement in symptoms of IBS.

Drotaverine is an antispasmodic that has been successfully used in the management of IBS for many years. It is a musculotropic agent that has antispasmodic activity and regulatory effects on the bowel function. It directly normalises dysmotility of GI smooth muscles. It is devoid of anticholinergic side effects, such as dry mouth, blurred vision, and impaired micturition. The incidence of side effects caused by Drotaverine has not been demonstrated to be higher than that of a placebo. Also, Drotaverine has fastest onset of action ie it takes about 5-12 minutes for pain relief compared to 1-2 hours with other agents like dicyclomine, hyoscine or mebeverine.

Moreover Drotaverine has been shown to provide global relief in abdominal pain. Also it has been found to improve stool frequency and flatulence. Drotaverine has shown significant augmentation of the rectal threshold for discomfort and pain in patients with IBS, indicating to its role in improving visceral hypersensitivity in these patients.²⁶Ruepert L, Quartero AO, de wit NJ, et al. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database SystRev2011 (8) . Arti clenumber : CD003460 . DOI:10:1002/14651858 CD003460.pub3.   Its efficacy and tolerability have been demonstrated over 40 years and its clinical usage continue in more than 45 countries.

Psychotropic Agents

The rationale for the use of psychotropic agents in irritable bowel syndrome is the co-existence of psychological traits in patients presenting to physicians, their success in chronic pain and, to a lesser extent, the peripheral actions of the medication on gut sensation and motility, actions which are poorly substantiated in the literature. To date, psychotropic (tricyclic antidepressant) agents have probably been best tested in irritable bowel syndrome patients with pain and diarrhoea. However, there is increasing interest in the potential application of selective serotonin re-uptake inhibitors (SSRI), which tend not to cause constipation and may even induce diarrhoea in some patients. One uncontrolled study supports the efficacy of selective serotonin re-uptake inhibitors, as well as tricyclic antidepressants, in the treatment of patients with irritable bowel syndrome. A recent meta-analysis of nine studies (eight with tricyclics and one with mianserin, all studies being of moderate quality) concluded that antidepressants are effective in irritable bowel syndrome patients. The only non-tricyclic antidepressant so far tested in a double blind, placebo-controlled study is mianserin, which seems to be as effective as tricyclic agents. Psychotropic agents are indicated for significant depression as well as for their neuromodulatory and analgesic properties. The effects of amitriptyline on oesophageal and rectal sensory thresholds and compliance in healthy individuals were not significant, and further studies are needed in patients with functional disorders. Typically, lower dosages are needed than those used in the treatment of depression (e.g. 10-25 mg amitriptyline or 50 mg desipramine). Because antidepressants must be used on a continual rather than an as-needed basis, they are generally reserved for patients having frequently recurrent or continual symptoms.²⁶Ruepert L, Quartero AO, de wit NJ, et al. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database SystRev2011 (8) . Arti clenumber : CD003460 . DOI:10:1002/14651858 CD003460.pub3.  

Hypnotherapy and Other Psychological Treatments

Psychological treatments are not required by all patients. There are four approaches to psychological therapy: relaxation, hypnosis, cognitive behavioral therapy and brief psychotherapy. Some published data support the efficacy of hypnotherapy and brief psychotherapy over placebo and standard medical care. However, a systematic review of the literature concluded that the efficacy has not been established because of methodological inadequacies in the studies. Eight studies reported that psychological treatments were superior to control therapy and five failed to find a significant effect. Factors favouring a response to psychotherapy are predominant diarrhoea and pain, overt psychiatric symptoms and intermittent pain exacerbated by anxiety or stress. In contrast, patients with constant abdominal pain respond poorly to psychotherapy or hypnotherapy. Non-anxious, non-depressed patients respond best to hypnotherapy. The role of psychological treatments has been discussed in a recent review. More data are required to identify the contribution of different psychological treatments to the management of irritable bowel syndrome and to identify features that predict a positive response.²⁷Kennedy T, Jones R, Darnley S, et al. Cognitive behaviour therapy in addition to antispasmodic treatment for irritable bowel syndrome in primary care: randomized controlled trial. BMJ. 2005, Aug; 38545. 505764. 06.  

Tegaserod

The selective 5-HT4 receptor agonist tegaserod is indicated for woman with IBS whose primary bowel symptom is constipation. Tegaserod is the first in a novel class of drugs (aminoguanidine indoles) designed to be similar in structure to serotonin and to act selectively at 5-HT4 receptors in the GI tract. Tegaserod accelerates overall GI transit in healthy subjects and promotes gastric emptying, small bowel transit and colonic transit in IBS-C patients. Tegaserod was found to reduce the firing rate of spinal afferents in vivo, supporting its role in the modulation of visceral sensitivity. Tegaserod also increased faecal water and intestinal secretion in female subjects. The efficacy of tegaserod has been evaluated in several large, multicentre, randomised, double-blind, placebo-controlled trials. In these trials, patients with IBS-C received placebo or tegaserod (2 or 6 mg twice daily) for 12 weeks. Two of the trials included 4-week follow-up without medication. When compared with placebo, tegaserod 6 mg twice daily produced statistically significant improvement in the Subject’s Global Assessment (a validated 5-point ordinal scale) of relief (overall symptom improvement), as well as in the single symptoms of abdominal pain/discomfort, number of bowel movements and stool consistency. Significant improvement in daily bloating scores was also observed in two of these trials, and one study showed that tegaserod-treated patients experienced a significant reduction in the number of days with straining, compared with controls. More recently, the efficacy of tegaserod was evaluated in randomised controlled trials among Asian-Pacific and Nordic populations with IBS whose primary bowel habits were not diarrhoea. In both studies, patients received either tegaserod 6 mg b.i.d. or placebo for 12 weeks. The results showed that the mean proportion of patients with overall satisfactory relief was statistically significantly greater in the tegaserod group compared with placebo for the majority of the study period. Reductions in the number of days with at least moderate abdominal pain/discomfort, bloating, no bowel movements and hard/lumpy stools were also greater in the tegaserod group. Tegaserod was well tolerated, with diarrhoea and headache being the most frequently reported adverse effects.²⁷Prather CM, Camilleri M, Zinsmeister AR, et al. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology. 2000; 118: 463-8.   ²⁹Petrig C, Templeton J, Matzinger D, et al. Effect of tegaserod on gastrointestinal transit in male and female subjects. Gut. 2002; 51(Suppl. III): A138.  

Alosetron

Alosetron is a selective 5-HT3 antagonist that was approved for the treatment of woman with irritable bowel syndrome whose predominant bowel symptom was diarrhoea. 5-HT3 receptors are cation channels that modulate visceral pain, colonic transit and gastrointestinal secretion. Alosetron delays colonic transit and reduces colonic sensation in irritable bowel syndrome patients with diarrhoea. Alosetron reduced arterial hypotension in response to noxious colorectal distensions in experimental animal models of visceral pain. Alosetron was associated with a larger proportion of women reporting adequate relief of pain relative to placebo (41% vs. 29% and 41% vs. 26% in the two studies). Bowel movements (frequency, consistency and urgency) were typically improved within 1 week of starting therapy. Constipation was significantly more common amongst women receiving alosetron compared to placebo (average 28% vs. 5%). It was suggested that alosetron should not be used in irritable bowel syndrome with constipation. Colonic obstructions related to constipation requiring surgery were reported with the use of alosetron, and the medication was withdrawn from the market in November 2000. Another significant adverse event that was reported, but had an unclear prevalence and relationship to treatment with alosetron, was acute ischaemic colitis. Alosetron is best used in women with severe IBS and diarrhoea who don’t respond to convention therapy.³⁰Krause R, Ameen V, Gordon SH, et al. A randomized, double-blind, placebocontrolled study to access efficacy & safety 0.5mg and 1mg alosetron in women with severe diarrhoea-predominant IBS. Am J Gastroenterol. 2007; 102(8):1709-1719.  

Linaclotide

Linaclotide, a minimally absorbed, 14-amino acid peptide guanylate cyclase-C agonist structurally related to the endogenous guanylin peptide family, binds to and activates GC-C on the luminal surface of the intestinal epithelium. Activation of GC-C results in generation of cyclic guanosine monophosphate (c G M P ), which is increased both intracellularly and extracellularly. The increase in cGMP within intestinal epithelial cells triggers a signal transduction cascade activating the cystic fibrosis transmembrane conductance regulator. This activation causes secretion of chloride and bicarbonate into the intestinal lumen, resulting in increased luminal fluid secretion and an acceleration of intestinal transit. Linaclotide accelerated colonic transit and improved abdominal pain and constipation associated with IBS-C. Linaclotide’s effects are believed to be a result of GC-C mediated elevation of extracellular cGMP, which has been shown to reduce the firing of afferent pain fibers in ex-vivo models of visceral nociception. It is conceivable that improvements in constipation may also contribute to the effects of linaclotide on abdominal symptoms. Linaclotide is approved for adults with IBSC at a dose of 290 mcg once daily. Use of linaclotide is contraindicated in paediatric patients.

In several clinical trials patients with IBS-C, linaclotide treatment resulted in significantly greater percentages of patients who experienced improvements in abdominal and bowel symptoms compared with placebo treatment. Linaclotide improved worst abdominal pain as demonstrated by a significant decrease in absolute worst abdominal pain score and a greater proportion of patients reporting ≥30 % reduction in abdominal pain. A 30% reduction in pain score has been suggested as the threshold for a moderately clinically important within-group improvement, based on anchoring methods linking such improvements to patient reports of feeling ” much better ” or ” much improved “. In addition to abdominal pain, linaclotide treatment resulted in significant improvements in other key abdominal symptoms, including discomfort, fullness, cramping and bloating.³¹Chey W D, Lembo A J, Lavins B J et al. Linaclotide for Irritable Bowel Syndrome With Constipation: A 26-Week, Randomized, Double-blind, Placebo- Controlled Trial to Evaluate Efficacy and Safety. The American Journal of Gastroenterology. 2012, Nov., Volume 107.   ³²Rao S, Lembo A J, Shiff S J, et al. A 12-Week, Randomized, Controlled Trial With a 4-Week Randomized Withdrawal Period to Evaluate the Efficacy and Safety of Linaclotide in Irritable Bowel Syndrome With Constipation. The American Journal of Gastroenterology. 2012, Nov.; Volume 107.  

Lubiprostone

Lubiprostone is a locally acting type-2 chloride channel (CIC-2) activator that activates CICI-2 in the apical membrane of the intestine. This results in increased excretion of chloride ions into the intestinal lumen, which leads to passive transport of sodium and water. Increased intestinal fluid secretion stimulates motility in the intestine. Lubiprostone is approved for women 18 years of age and older at a dose of 8mcg twice daily. Approval for lubiprostone is based on two similar, randomised, double-blind, placebo-controlled phase 3 trials in adults meeting the criteria for constipation-predominant IBS. During the study, more patients assigned to lubiprostone reported improvement in abdominal discomfort and pain, abdominal bloating, bowel movement frequency, stool consistency and straining, but these improvements were significant for only part of the study duration. The most frequently reported adverse events were nausea (8% with lubiprostone and 4% with placebo) and diarrhoea (6% with lubiprostone and 4%with placebo).³³Lunsford T N, Harris L A. Lubiprostone: evaluation of the newest medication for the treatment of adult women with constipation-predominant irritable bowel syndrome. International Journal of Women’s Health. 2010; 2 361-74.  

Rifaximin

Rifaximin is an oral, nonsystemic, broad-spectrum antibiotic that targets the gut and is associated with a low risk of bacterial resistance. It has shown efficacy in small-scale studies of IBS. It has also been studied in several well-designed randomised, controlled trials for IBS. The two largest trials, TARGET 1 and TARGET 2, were identical in design. The results of these two phase 3 studies showed that treatment with rifaximin at a dose of 550 mg three times daily for 14 days provides better relief of symptoms of IBS than does placebo for up to 10 weeks after completion of therapy.³⁴Pimentel M, Lembo A, Chey W D et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011; 364:22-32.   ³⁵Menees SB, Maneerattannaporn M, Kim HM, Chey WD.The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and metaanalysis. Am J Gastroenterol. 2012; 107(1):28-35.   ³⁶John Jolley. High-dose rifaximin treatment alleviates global symptoms of irritable bowel syndrome.Clinical and Experimental Gastroenterology. 2011:443-48.  

Other New Therapies Under Development

Pharmaceutical companies have identified several agents with visceral analgesic properties that have stimulated much interest in the field of irritable bowel syndrome therapy. Several novel approaches are undergoing evaluation in phase II or phase III trials. Potential treatments include the kappa opioid agonist, fedotozine, other 5-HT3 and 5-HT4 antagonists, other serotonergic agents and neurokinin (NK1 and NK3) receptor antagonists. Other drugs undergoing research include an alpha2-adrenergic agonist, clonidine, a 5-HT1 agonist, buspirone, and a selective serotonin re-uptake inhibitor, citalopram. Similarly, promising results with traditional Chinese medicines need to be further studied. It is hoped that future studies will incorporate the evaluations of symptom, physiological, behavioural and psychological end-points when evaluating clinical efficacy. This will help to establish a greater understanding of these medications and their mechanisms of action.²²Mertz HR. Irritable bowel syndrome. N Engl J Med. 2003; 349: 2142.  

Drotaverine

Evidence Based Studies

According to the study by Pap et al³⁸Pap A, Hamvas J, Filiczky I, et al. Beneficial effect of drotaverine in irritable bowel syndrome (IBS). Gastroenterology. 1998, April; Vol. 114, Supplement 1, Page A 818.   drotaverine was effective in decreasing pain in 47% of IBS patients treated with drotaverine as compared with 3% in the placebo group. Bloating was also reduced (Figure 2).

According to Rooprai. R et al³⁹Rai RR, Dwivedi M, Kumar N. Efficacy and safety of drotaverine hydrochloride in irritable bowel syndrome: A randomized double-blind placebo-controlled study. Saudi J Gastroenterol 2014;20(6):378-82  , pain frequency and severity was decreased in 77.7% of IBS patients in drotaverine group as compared to 30.6% in placebo group and significant improvement in global relief in abdominal pain as perceived by the patient (85.9% vs 39.5%) and the clinician (82.4% vs 36.5%) as compared to placebo. Significant improvement in stool frequency in 44.7% patients in the drotaverine group as compared to 15.3% in the placebo group (Figure 3).

According to the study by Khalif et al⁴⁰Khalif IL, Quigley EM, Makarchuk PA, et al. Interactions between symptoms  , drotaverine led to a significant augmentation of the rectal threshold for discomfort/pain among IBS subjects with predominant diarrhoea. This placebo-controlled study investigated relationships between symptomatic, motility and visceral sensory effects of the antispasmodic pharmacological agents (drotaverine). Drotaverine has been widely used as a spasmolytic agents in gastroenterology, obstetrics, urology and surgery and it has potentially effective in Irritable Bowel Syndrome.

According to the randomised placebo controlled trial done by Misra et al⁴¹Asmar A, Mohandas R, Wingo CS. A physiologic-based approach to the treatment of a patient with hypokalemia. Am J Kidney Dis. 2012 Sep;60(3):492-7.   drotaverine gives relief in frequency and severity of abdominal pain, improvement in bowel habit. Pain frequency and severity decreased significantly with drotaverine as compared with placebo in 31.4% and 71.4% in 2nd and 4th week respectively (Figure 4). There was global relief in abdominal pain as perceived by the patient and the clinician (Figure 5) in the drotaverine group as compared with placebo (74% versus 37.1% respectively). Improvement in stool frequency also occurred in the drotaverine group (25.7%) in comparison to placebo group (2.8%) (Figure 6).

Summary

IBS is a prevalent GI disorder of diverse pathophysiology. Recent guidelines have assessed and graded the evidence that supports various diagnostic approaches and therapeutic options for IBS. IBS can be diagnosed confidently through the identification of the appropriate symptoms and the exclusion of alarm features.

Younger patients who fulfill symptom-based criteria for IBS and have no alarm features do not need to undergo exhaustive testing to exclude organic diseases. After the diagnosis of IBS has been established, management should focus on patient reassurance, education and amelioration of symptoms. This is best achieved through a well-developed patient physician relationship with a clear delineation of realistic goals and expectations. Medical therapies that target the predominant symptoms of bloating, pain abdomen, diarrhoea and constipation are appropriate first-line agents.

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