Advances in the Therapies of Irritable Bowel Syndrome

Irritable bowel syndrome: Need for advanced therapeutic options

Irritable bowel syndrome (IBS) refers to a significantly prevalent functional bowel disorder affecting about 11% of the global population.¹Lacy BE, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therapeutic Advances in Gastroenterology. 2009;2(4):221-238.   ²Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clinical Epidemiology. 2014;6:71-80.    Prevalence figures from Asia alone range from 3.7% to 22%.³Rai RR, Dwivedi M, Kumar N. Efficacy and Safety of Drotaverine Hydrochloride in Irritable Bowel Syndrome: A Randomized Double-Blind Placebo-Controlled Study. Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association. 2014;20(6):378-382.

In addition to the considerable prevalence, this condition carries a negative impact on the patient’s quality of life as well (despite being a non-life threatening disease).¹Lacy BE, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therapeutic Advances in Gastroenterology. 2009;2(4):221-238.   The patients affected with this syndrome usually express significantly elevated levels of various psychological traits (Figure 1).⁴Whitehead WE, Engel BT, Schuster MM. Digest Dis Sci. 1980; 25: 404.

The deteriorated quality of life experienced by the affected patients can be attributed to the bothersome symptoms of the syndrome; about 70% of the patients with IBS complain of abdominal pain or discomfort severely affecting their quality of life.³Rai RR, Dwivedi M, Kumar N. Efficacy and Safety of Drotaverine Hydrochloride in Irritable Bowel Syndrome: A Randomized Double-Blind Placebo-Controlled Study. Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association. 2014;20(6):378-382.    Additionally, inadequate symptom control can become a cause of impaired patient-doctor relationship, prompting the patients to seek further opinions. This may ascribed to the long course and high relapse rates of the syndrome. Over half of the patients report the same symptom profile after 1 and 7 years and a further 25% complain of persistent minor IBS symptoms.=⁵Annahazi A, Roka R, Rosztoczy A, Wittmann T. Role of antispasmodics in the treatment of irritable bowel syndrome. World Journal of Gastroenterology : WJG. 2014;20(20):6031- 6043.    In order to deduce an appropriate treatment approach, the reasons behind the manifestations of the syndrome need to be explored.

An insight into the pathophysiology of irritable bowel syndrome

Irritable bowel syndrome is believed to be associated with a multifactorial pathophysiology particularly involving disturbances of the brain-gut-axis such as abnormal gastrointestinal motor functions, visceral hypersensitivity, autonomic dysfunction and mucosal inflammation.⁶Andresen V, Camilleri M. Irritable Bowel Syndrome Recent and Novel Therapeutic Approaches. Drugs. 2006; 66: 1073.    The visceral hypersensitivity is considered a cause of abdominal discomfort or pain and gastrointestinal motor disturbances are usually responsible for diarrhea or constipation. However, these gastrointestinal motor disturbances (changes in intestinal transit) cannot justify mixed or alternating IBS.

In an attempt to further deduce the pathophysiology of IBS, it has been hypothesized that the brains of healthy individuals are superior in activating endogenous pain inhibition areas compared to that of patients with IBS. This may imply a genetic predisposition to IBS.⁷Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis, treatment, and evidencebased medicine. World Journal of Gastroenterology : WJG. 2014;20(22):6759-6773.

The abnormalities associated with IBS have also been referred secondary manifestations, rather than primary, after psychological disturbances. Nevertheless, absence of significant psychological overlay in some of the affected patients signifies a partial psychological association.⁷Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis, treatment, and evidencebased medicine. World Journal of Gastroenterology : WJG. 2014;20(22):6759-6773.

The possible association of emotional disturbances and gastrointestinal manifestations is depicted in Figure 2.⁸Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47:861- 869.

The central nervous system is involved in modulation of various functions such as secretion, motility, and blood flow. Signals from the gut, in turn, regulate reflexes. Activation of afferent pathways, constitutes the perception of events in the gut with subsequent modulation of information at different levels, peripheral as well as central.⁷Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis, treatment, and evidencebased medicine. World Journal of Gastroenterology : WJG. 2014;20(22):6759-6773.

A network comprising of integrative brain structures such as subregions of the hypothalamus amygdala, and periaqueductal grey is involved in generation of response to stress.8 Input is received from visceral and somatic afferents and from cortical structures (medial prefrontal cortex, and subregions of the anterior cingulate and insular cortices).⁸Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47:861- 869.

The analysis of regional cerebral blood flow during rectal distention has revealed considerable activation of the anterior cingulate cortex, amygdala and dorsomedial frontal cortex in patients with IBS.=⁷Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis, treatment, and evidencebased medicine. World Journal of Gastroenterology : WJG. 2014;20(22):6759-6773.    This may further explain the association of gastrointestinal symptoms with psychological disturbances. In line with this, the integrative network (after receiving the input) provides outputs to the pituitary and pontomedullary nuclei in which the former mediates the neuroendocrine output and the latter is responsible for autonomic output to the body. This process is regulated by feedback control via ascending monoaminergic projections from these brain stem nuclei and via circulating glucocorticoids (GCs), which are involved in exerting an inhibitory action via central GC receptors located in the medial prefrontal cortex and hippocampus. The outputs particularly include responses of the autonomic nervous system among the other actions, thereby establishing an emotional motor system involved in regulation of gastrointestinal symptoms encountered in response to various stresses..⁸Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47:861- 869.    This, in turn may corroborate the smooth muscle spasm causing abdominal pain as a predominant symptom among patients with IBS.³Rai RR, Dwivedi M, Kumar N. Efficacy and Safety of Drotaverine Hydrochloride in Irritable Bowel Syndrome: A Randomized Double-Blind Placebo-Controlled Study. Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association. 2014;20(6):378-382.

Last but not the least, few evidences have also related lactose intolerance with exaggeration of IBS symptoms.⁹Vernia P, Ricciardi MR, Frandina C, Bilotta T, Frieri G. Lactose malabsorption and irritable bowel syndrome. Effect of a long-term lactose-free diet. Ital J Gastroenterol. 1995 Apr;27(3):117-21.    ¹⁰Dainese R, Casellas F, Marine-Barjoan E, Vivinus-Nebot M, Schneider SM, Hebuterne X, Piche T. Perception of lactose intolerance in irritable bowel syndrome patients. Eur J Gastroenterol Hepatol. 2014 Oct;26(10):1167-75.    The following section addresses this arguable association.

Lactose intolerance and IBS: The underappreciated concern

The significance of lactose malabsorption in IBS is not completely elucidated. Nevertheless, the patients with IBS frequently experience lactose intolerance.¹⁰Dainese R, Casellas F, Marine-Barjoan E, Vivinus-Nebot M, Schneider SM, Hebuterne X, Piche T. Perception of lactose intolerance in irritable bowel syndrome patients. Eur J Gastroenterol Hepatol. 2014 Oct;26(10):1167-75.    In this context, a study aimed to evaluate the prevalence of lactose intolerance among patient with IBS. Majority of the patients (about 68%) demonstrated lactose malabsorption.⁹Vernia P, Ricciardi MR, Frandina C, Bilotta T, Frieri G. Lactose malabsorption and irritable bowel syndrome. Effect of a long-term lactose-free diet. Ital J Gastroenterol. 1995 Apr;27(3):117-21.

It should be noted that lactose malabsorption may result in abdominal symptoms indistinguishable from IBS.⁹Vernia P, Ricciardi MR, Frandina C, Bilotta T, Frieri G. Lactose malabsorption and irritable bowel syndrome. Effect of a long-term lactose-free diet. Ital J Gastroenterol. 1995 Apr;27(3):117-21.    Lactose intolerance is dependent upon factors such as, intestinal flora, gastrointestinal motility, small intestinal bacterial overgrowth and sensitivity of the gastrointestinal tract to the generation of gas and other fermentation products of lactose digestion. Moreover, about two-thirds of the global population experiences a decrease in lactase synthesis (genetically programmed decrease) after weaning. This is referred to as primary lactase deficiency. Among those with lactase persistence, health issues such as gastrointestinal infection, inflammatory bowel disease, abdominal surgery are also capable of causing lactase activity which is known as secondary lactase deficiency.¹¹Deng Y, Misselwitz B, Dai N, Fox M. Lactose Intolerance in Adults: Biological Mechanism and Dietary Management. Nutrients. 2015 Sep 18;7(9):8020-35.   

In furtherance, approximately half of patients with functional gastrointestinal symptoms in a lactase deficient population report intolerance to dairy products.¹²Zheng X, Chu H, Cong Y, Deng Y, Long Y, Zhu Y, Pohl D, Fried M, Dai N, Fox M. Selfreported lactose intolerance in clinic patients with functional gastrointestinal symptoms: Prevalence, risk factors, and impact on food choices. Neurogastroenterol. Motil. 2015; 27:1138-1146.

This may be because lactase deficiency results in accumulation of unabsorbed lactose in the intestinal tract, which can lead to lactose intolerance in susceptible individuals. The intestinal water content increases due to the elevated osmotic load. Lactose is then fermented by the colonic microbiome resulting in production of short chain fatty acids and gas.

The above processes take place for other poorly-absorbed constituents as well, such as fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) which are present ubiquitously in diet. Patients with IBS have been particularly observed to be at risk both self-reporting dairy intolerance and experiencing symptoms after lactose and FODMAP ingestion.¹¹Deng Y, Misselwitz B, Dai N, Fox M. Lactose Intolerance in Adults: Biological Mechanism and Dietary Management. Nutrients. 2015 Sep 18;7(9):8020-35.    In this regard, a randomized, controlled, single-blind, cross-over trial comparing the effects of a diet low in FODMAPs with that of Australian diet among patients with IBS is worth mentioning. Patients who received a diet low in FODMAPs had lower overall gastrointestinal symptom scores compared to those receiving the Australian diet (Figure 3). The former group of patients also reported reduction in bloating, pain, and passage of wind.¹³Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology. 2014 Jan;146(1):67-75.e5.

In view of the above, treatment of IBS should not just be focused upon relieving the predominant symptom of abdominal pain, but also be individualized according to the presence or absence of lactose intolerance.¹Lacy BE, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therapeutic Advances in Gastroenterology. 2009;2(4):221-238.

In India oral Lactase enzymes are available which can be taken to digest milk and dairy. Generally IBS patients are advised to avoid milk and dairy, which further may decrease the quality of life of patients and may also effect bone health in the long run.

Advanced therapeutic options in IBS

Therapeutic strategies for IBS usually include relieving stress, alteration in eating habits and pharmacologic management. In context of medical management of the syndrome, antispasmodics constitue the mainstay of the therapy.³Rai RR, Dwivedi M, Kumar N. Efficacy and Safety of Drotaverine Hydrochloride in Irritable Bowel Syndrome: A Randomized Double-Blind Placebo-Controlled Study. Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association. 2014;20(6):378-382.    Antispasmodics or spasmolytics aim at reducing the defecation symptoms. This is achieved by:⁵Annahazi A, Roka R, Rosztoczy A, Wittmann T. Role of antispasmodics in the treatment of irritable bowel syndrome. World Journal of Gastroenterology : WJG. 2014;20(20):6031- 6043.

• Increasing colonic transit time
• Improving stool consistency
• Reducing stool frequency.

Commonly prescribed antispasmodics for the management of IBS include hyoscyamine, dicyclomine, propantheline, and mebeverine. However, these drugs come with a drawback of anticholenergic side effects, which has led to limited use of antispasmodics.³Rai RR, Dwivedi M, Kumar N. Efficacy and Safety of Drotaverine Hydrochloride in Irritable Bowel Syndrome: A Randomized Double-Blind Placebo-Controlled Study. Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association. 2014;20(6):378-382.    Anticholinergic side-effects can be of 2 types: peripheral and central (Box 1). Peripheral side-effects can be diagnosed easily and may not appear serious. However, they have the potential of causing a plethora of medical complications ranging from ulceration of the gums and respiratory problems to hyperthermia and myocardial infarction. Central side-effects are usually cerebral. The side-effects (both central and peripheral), although considered minor, are capable of exerting considerable impairment in both physical and mental domains of life.¹⁴Lieberman JA. Managing Anticholinergic Side Effects. Primary Care Companion to The Journal of Clinical Psychiatry. 2004;6(suppl 2):20-23.

In view of the limitations of the conventional anti-cholinergic, antispasmodics, searching for an alternative antispasmodic for alleviating the symptoms of IBS is the need of the hour.¹⁵Kulkarni KS. Antispasmodics – A New Perspective. JAMA India. 2001;4(8): 119-121.

Drotaverine, an antispasmodic, needs elucidation in this regard considering the appreciable relaxing effect on intestinal smooth muscle associated with its use without the occurrence of anticholinergic side-effects.³Rai RR, Dwivedi M, Kumar N. Efficacy and Safety of Drotaverine Hydrochloride in Irritable Bowel Syndrome: A Randomized Double-Blind Placebo-Controlled Study. Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association. 2014;20(6):378-382.

RationalE and role of drotaverine in IBS

Drotaverine is a selective inhibitor of phosphodiesterase isoenzyme IV. Phosphodiesterase isoenzymes are involved in regulation of smooth muscle relaxation of the gastrointestinal tract. This provides the rationale for administration of drotaverine in spastic and motility disorders of the smooth muscle.¹⁶Misra SC, Pandey RM. Efficacy of drotaverine in irritable bowel syndrome: A double blind, randomized, placebo-controlled clinical trial. AJG. 2000; 95(9):2544.

Drotaverine by its PDE-4 inhibitory and Ca-calmodulin complex inhibitory activity, relaxes the smooth muscle of the gut and helps in relieving abdominal pain. It directly normalises the dysmoltility.Drotaverine is well tolerated and safe and provides global relief from abdominal pain in IBS. It shows significant improvement in stool frequency, consistency, urgency, and flatulence. Drotaverine has quick onset of action; free from anti-cholinergic side effects.¹⁷Drotaverine. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/drotaverine. Accessed on: 29-5-2017.  

Although there is a paucity of data regarding drotaverine administration for management of IBS, few studies have been conducted to evaluate its efficacy. A double blind, randomized, placebo-controlled clinical trial evaluating the efficacy of drotaverine in relieving abdominal pain and bowel disturbance among 70 patients with IBS demonstrated striking outcomes. Significant proportion of patients receiving drotaverine compared to those who received placebo demonstrated reduction in pain frequency at the end of 2 and 4 weeks (Figure 4). Addtionally, 71.4% of the patients in the drotaverine group demonstrated lower pain scores compared to the 31.4% in the placebo group. The former group also showed global relief in abdominal pain as perceived by the patient and the clinician (Figure 5). Improvement in stool frequency was observed in significant proportion of patients assigned to receive drotaverine (25.7% versus 2.8%). Adverse event of the drug was not encountered in any of the patient.¹⁶Misra SC, Pandey RM. Efficacy of drotaverine in irritable bowel syndrome: A double blind, randomized, placebo-controlled clinical trial. AJG. 2000; 95(9):2544.

Another study investigated the efficacy drotaverine hydrochloride 80 mg tablet for symptomatic relief of patients with IBS. A total of 180 patients were randomized to receive either drotaverine 80 mg tablet TID or placebo for a duration of 4 weeks. Results at the end of 2^nd, 3^rd, and 4^th weeks are depicted in Table 1.

Similarly, 77.7% of the patients in the drotaverine group demonstrated significant reduction in pain severity after 4 weeks. Global relief in abdominal pain (as perceived by the patient) was observed in 85.9% of the patients in drotaverine group. Patients receiving drotaverine also showed considerable improvement in stool frequency.³Rai RR, Dwivedi M, Kumar N. Efficacy and Safety of Drotaverine Hydrochloride in Irritable Bowel Syndrome: A Randomized Double-Blind Placebo-Controlled Study. Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association. 2014;20(6):378-382.

Conclusion

Irritable bowel syndrome, a significantly prevalent condition, exerts severe impact on the quality of life of those affected. The psychological issues associated with the syndrome are usually attributed to the predominant symptom; abdominal pain. An insight into the pathophysiologic mechanism reveals that psychological disturbances occurring prior to the diagnosis of the disease are also linked with gastrointestinal symptoms; thus, implying a vice-versa association of psychological impact and gastrointestinal symptoms among patients with irritable bowel syndrome. Moreover, patients with irritable bowel syndrome are usually at risk of developing lactose intolerance that demonstrates overlapping symptoms. Management of the syndrome usually includes antispasmodics as abdominal pain generally encountered in the disorder is a result of smooth muscle spasm arising due to various pathophysiological mechanisms; nevertheless, these drugs are associated with anticholinergic side-effects. Drotaverine, in this regard, seems an appropriate approach as it exhibits remarkable efficacy in relieving the spasms and is not associated with any adverse event.

Since most of the IBS patients are instructed to avoid milk and dairy products, oral lactase enzyme supplements can help these patients to digest milk and dairy.

References

1. Lacy BE, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therapeutic Advances in Gastroenterology. 2009;2(4):221-238.
2. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clinical Epidemiology. 2014;6:71-80.
3. Rai RR, Dwivedi M, Kumar N. Efficacy and Safety of Drotaverine Hydrochloride in Irritable Bowel Syndrome: A Randomized Double-Blind Placebo-Controlled Study. Saudi Journal of Gastroenterology : Official Journal of the Saudi Gastroenterology Association. 2014;20(6):378-382.
4. Whitehead WE, Engel BT, Schuster MM. Digest Dis Sci. 1980; 25: 404.
5. Annaházi A, Róka R, Rosztóczy A, Wittmann T. Role of antispasmodics in the treatment of irritable bowel syndrome. World Journal of Gastroenterology : WJG. 2014;20(20):6031- 6043.
6. Andresen V, Camilleri M. Irritable Bowel Syndrome Recent and Novel Therapeutic Approaches. Drugs. 2006; 66: 1073.
7. Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis, treatment, and evidencebased medicine. World Journal of Gastroenterology : WJG. 2014;20(22):6759-6773.
8. Mayer EA. The neurobiology of stress and gastrointestinal disease. Gut. 2000;47:861– 869.
9. Vernia P, Ricciardi MR, Frandina C, Bilotta T, Frieri G. Lactose malabsorption and irritable bowel syndrome. Effect of a long-term lactose-free diet. Ital J Gastroenterol. 1995 Apr;27(3):117-21.
10. Dainese R, Casellas F, Mariné-Barjoan E, Vivinus-Nébot M, Schneider SM, Hébuterne X, Piche T. Perception of lactose intolerance in irritable bowel syndrome patients. Eur J Gastroenterol Hepatol. 2014 Oct;26(10):1167-75.
11. Deng Y, Misselwitz B, Dai N, Fox M. Lactose Intolerance in Adults: Biological Mechanism and Dietary Management. Nutrients. 2015 Sep 18;7(9):8020-35.
12. Zheng X, Chu H, Cong Y, Deng Y, Long Y, Zhu Y, Pohl D, Fried M, Dai N, Fox M. Selfreported lactose intolerance in clinic patients with functional gastrointestinal symptoms: Prevalence, risk factors, and impact on food choices. Neurogastroenterol. Motil. 2015; 27:1138–1146.
13. Halmos EP, Power VA, Shepherd SJ, Gibson PR, Muir JG. A diet low in FODMAPs reduces symptoms of irritable bowel syndrome. Gastroenterology. 2014 Jan;146(1):67-75.e5.
14. Lieberman JA. Managing Anticholinergic Side Effects. Primary Care Companion to The Journal of Clinical Psychiatry. 2004;6(suppl 2):20-23.
15. Kulkarni KS. Antispasmodics – A New Perspective. JAMA India. 2001;4(8): 119-121.
16. Misra SC, Pandey RM. Efficacy of drotaverine in irritable bowel syndrome: A double blind, randomized, placebo-controlled clinical trial. AJG. 2000; 95(9):2544.
17. Drotaverine. Available at: https://pubchem.ncbi.nlm.nih.gov/compound/drotaverine. Accessed on: 29-5-2017.