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Symptomatic Management of Irritable Bowel Syndrome

Irritable Bowel Syndrome and its Burden

Irritable bowel syndrome is one of the most common functional gastrointestinal disorders, marked by alteration in bowel habits without any underlying organic pathology. The globally conducted population based studies have revealed the prevalence of IBS between 3-22%, which may go as high as 30% in some parts of the world. Even in the Asia-Pacific region, there has been a surge in prevalence rates of IBS, particularly in developing countries.1Basandra S, Bajaj D. Epidemiology of Dyspepsia and Irritable Bowel Syndrome (IBS) in Medical Students of Northern India. Journal of Clinical and Diagnostic Research : JCDR. 2014;8(12):JC13-JC16.   In India, the prevalence of IBS has been reported to be 4% in Northern rural communities and nearly 7.6% in Mumbai.2Makharia GK, Verma AK, Amarchand R, Goswami A, Singh P,Agnihotri A, Suhail F, Krishnan A. Prevalence of Irritable Bowel Syndrome: A Community Based Study From Northern India. Journal of Neurogastroenterology and Motility. 2011;17(1):82-87.   Besides, it has been observed that it has a bimodal peak of occurrence in the third and fourth decades of life and has a typical female gender predilection.3Spiller R, Aziz Q, Creed F, A Emmanuel, L Houghton, P Hungin, R Jones, D Kumar, G Rubin, N Trudgill, and P Whorwell. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut. 2007;56(12):1770-1798.   While in India, IBS is more common in young individuals, and show a male predominance.4Upadhyay R, Singh A. Irritable Bowel Syndrome: The Indian Scenario.Available from: http://citeseerx.ist.psu.edu/viewdoc/download?doi =10.1.1.671.361&rep=rep1&type=pdf. Accessed on: 28.4.16.  The prevalence of IBS measured in the community and even in the outpatient clinics is heterogeneous as the clinical criteria used might differ.2Makharia GK, Verma AK, Amarchand R, Goswami A, Singh P,Agnihotri A, Suhail F, Krishnan A. Prevalence of Irritable Bowel Syndrome: A Community Based Study From Northern India. Journal of Neurogastroenterology and Motility. 2011;17(1):82-87.   Although, IBS is generally not life threatening, it is chronic enough to worsen the quality of life of patients.5Lacy BE, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therapeutic Advances in Gastroenterology.2009;2(4):221-238.   The degree of impairment in these individuals is similar to that caused by major chronic disorders, such as diabetes, congestive heart failure, renal insufficiency, and hepatic cirrhosis.6El-Salhy M. Irritable bowel syndrome: Diagnosis and pathogenesis.World Journal of Gastroenterology : WJG. 2012;18(37):5151-5163.   Despite such profound effects, the pathogenesis of IBS is considered complex and only partially understood.7Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B,Corinaldesi R. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther. 2004 Jul;20 Suppl 2:1-9.  

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Pathogenesis of Irritable Bowel Syndrome

The pathogenesis of IBS is multifactorial and may be majorly ascribed to mechanisms that include altered gastrointestinal motility, increased visceral perception,and psychosocial factors.7Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B,Corinaldesi R. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther. 2004 Jul;20 Suppl 2:1-9.   8Camilleri M, Ford MJ. Review article: colonic sensorimotor physiology in health, and its alteration in constipation and diarrhoeal disorders.Aliment Pharmacol Ther. 1998 Apr;12(4):287-302.   9Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2001 Apr;280(4):G519-24   Other than these, several additional factors have also been recognized that may be linked to these classical mechanisms. Abnormal expulsion of intestinal gas followed by gas trapping and bowel distension may be conducive to abdominal discomfort/pain and bloating.7Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B,Corinaldesi R. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther. 2004 Jul;20 Suppl 2:1-9.   10Lasser RB, Bond JH, Levitt MD. The role of intestinal gas in functional abdominal pain. N Engl J Med. 1975 Sep 11;293(11):524-6.   Painful stimulation of the rectum may lead to aberrant activation of certain brain regions, suggestive of altered processing of afferent signals. Moreover, an acute gastrointestinal infection has been lately identified as a crucial etiological factor. The abdominal pain in such post-infectious cases and even in those with non-specific cause may be ascribed to lowgrade inflammatory infiltration and activation of mast cells in proximity to nerves in the colonic mucosa. Besides,role of changes in gut microflora, serotonin metabolism,and genetic factors in IBS pathophysiology has also emerged (table 1). These multiple factors together or individually are believed to contribute to the symptom complex experienced by the individuals with IBS.7Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B,Corinaldesi R. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther. 2004 Jul;20 Suppl 2:1-9.  

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Clinical Presentation and Current Diagnostic Criteria of Irritable Bowel Syndrome

The nature of IBS remains recurrent, characterized by chronic abdominal pain, discomfort, and bloating in the absence of any anatomical or biochemical abnormalities.11Chua ASB. Prevalence of Irritable Bowel Syndrome in Northern India.Journal of Neurogastroenterology and Motility. 2011;17(1):6-8.   If the alarming signs are not evident (such as weight loss, rectal bleeding, nocturnal symptoms, anemia, family history of colorectal cancer, inflammatory bowel disease), a positive diagnosis of IBS can be made based on the clinical symptoms using specific criteria, rather than exclusion of alternative diagnoses.4Upadhyay R, Singh A. Irritable Bowel Syndrome: The Indian Scenario.Available from: http://citeseerx.ist.psu.edu/viewdoc/download?doi =10.1.1.671.361&rep=rep1&type=pdf. Accessed on: 28.4.16.    11Chua ASB. Prevalence of Irritable Bowel Syndrome in Northern India.Journal of Neurogastroenterology and Motility. 2011;17(1):6-8.   The most accepted criteria for the diagnosis comprise the original Manning criteria and the subsequent series of “Rome foundation” defined criteria. The Rome III criteria clearly illustrates IBS as a disorder with an onset of at least 6 months prior to diagnosis, manifestation of recurrent abdominal pain or discomfort for at least 3 days per month over the last 3 months, and presence of two or more associated symptoms (box 1).5Lacy BE, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therapeutic Advances in Gastroenterology.2009;2(4):221-238.   11Chua ASB. Prevalence of Irritable Bowel Syndrome in Northern India.Journal of Neurogastroenterology and Motility. 2011;17(1):6-8.   This updated ROME III criteria also indicates that IBS can be classified into three predominant subtypes; IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), and mixed IBS (IBS-M).12Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis,treatment, and evidence-based medicine. World Journal of Gastroenterology : WJG. 2014;20(22):6759-6773.   While IBS-C and IBS-D have a similar impact on quality of life, bloating and diarrhea severely affects patient’s self-confidence, leading to withdrawal from social settings. Overall, since IBS negatively influences daily functioning, work, lifestyle, and interrupts sleep,patients should be promptly evaluated for a possible diagnosis.13Yoon SL, Grundmann O, Koepp L, Farrell L. Management of irritable bowel syndrome (IBS) in adults: conventional and complementary/ alternative approaches. Altern Med Rev. 2011 Jun;16(2):134-51.   The key to formulate a diagnosis of IBS is by taking a meticulous history and performing a general examination. Individuals presenting with features of organic disease (table 2) should be advised to undergo further evaluation.4Upadhyay R, Singh A. Irritable Bowel Syndrome: The Indian Scenario.Available from: http://citeseerx.ist.psu.edu/viewdoc/download?doi =10.1.1.671.361&rep=rep1&type=pdf. Accessed on: 28.4.16.   Besides, investigation of psychosocial issues accompanied by establishment of a positive diagnosis with reassurance to patients is essential in the management of IBS.14Talley NJ. Irritable bowel syndrome. Internal medicine journal.2006;36(11):724-728.  

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Management of Irritable Bowel Syndrome

Thorough management follows the diagnosis of IBS,and as the cause remains unclear, there is no discrete lesion to direct the therapy accordingly. As a result, the treatment of IBS generally emphasizes on symptoms’improvement, rather than disease modification or cure.15Sainsbury A, Ford AC. Treatment of irritable bowel syndrome:beyond fiber and antispasmodic agents. Therapeutic Advances in Gastroenterology. 2011;4(2):115-127.   Its management broadly comprises changes in eating abits, stress relief, and pharmacological therapy.16Rai 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.  

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An Insight into Non-Pharmacological Therapies

Lifestyle and diet are considered important factors,both at the initial and later stages of management, as these might trigger or exacerbate symptoms of IBS.Diet including wheat, resistant starch, caffeine, fructose,sorbitol, alcohol, and fizzy drinks has been implicated in affecting the severity of symptoms. On the other hand,increase in dietary fibre intake (which is not hydrolyzed by GIT enzymes) has often been suggested as a part of initial therapy. The chief dietary recommendations are summarized in box 2.17National Collaborating Centre for Nursing and Supportive Care (UK).Irritable Bowel Syndrome in Adults: Diagnosis and Management of Irritable Bowel Syndrome in Primary Care [Internet]. London: Royal College of Nursing (UK); 2008 Feb. (NICE Clinical Guidelines, No.61.) 7, Diet and lifestyle. Available from: http://www.ncbi.nlm.nih.gov/books/NBK51960/. Accessed on: 30.4.16.   Furthermore, lifestyle interventions involving physical activity can help in reducing stress and maintaining GI function, and may thereby ease some of the symptoms. For instance, pedaling a bicycle may prevent GI symptom aggravation and alleviates gas conditions. Moreover, stress-relieving therapies, such as relaxation techniques and training, hypnotherapy and cognitive-behavioral therapy have displayed potential role in alleviating IBS symptoms. Acupuncture is also known to induce physiological changes, in turn affecting various endogenous neurotransmitter systems.18Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis,treatment, and evidence-based medicine. World Journal of Gastroenterology : WJG. 2014;20(22):6759-6773.   These nonpharmacological strategies are not only advised initially in the therapeutic approach, but are also suggested in adjunct to the drug therapy.

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Pharmacotherapeutic Options for Irritable Bowel Syndrome

The available pharmacological treatment options are mainly symptom-targeted as there may be wide variation in the manifestations experienced.13Yoon SL, Grundmann O, Koepp L, Farrell L. Management of irritable bowel syndrome (IBS) in adults: conventional and complementary/ alternative approaches. Altern Med Rev. 2011 Jun;16(2):134-51.   The four major treatment goals for successful management of IBS comprise:

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Therefore, addressing the symptoms individually,despite their overlap, permits the physician to resort to an organized and appropriate medical therapy (table 3).19Occhipinti K, Smith JW. Irritable Bowel Syndrome: A Review and Update. Clinics in Colon and Rectal Surgery. 2012;25(1):46-52.  

Abdominal pain in IBS is considered the most distressing symptom and also the most frequent reasons of seeking medical care. The underlying cause of abdominal pain has been conventionally attributed to smooth muscle spasm. In light of this,antispasmodics have been integral and well-accepted part of therapy.16Rai 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.   These are also termed spasmolytics,directed at intestinal smooth muscle and affect visceral sensation than motility.20Khalif IL, Quigley EM, Makarchuk PA, Golovenko OV, Podmarenkova LF, Dzhanayev YA. Interactions between symptoms and motor and visceral sensory responses of irritable bowel syndrome patients to spasmolytics (antispasmodics). J Gastrointestin Liver Dis. 2009 Mar;18(1):17-22.   Drotaverine is one such musculotropic antispasmodic agent that exerts a good relaxing effect on intestinal smooth muscle, resulting in pain alleviation and is devoid of any anticholinergic side effects.16Rai 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.   21Mishra SC, Gupta K, Chatterjee N. Drotaverine in irritable bowel syndrome: A clinical review. Gastroenterology Today. 2001 October- December;5(4):186-188.  

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Role of drotaverine in relieving symptoms of irritable bowel syndrome

The preclinical pharmacokinetic and metabolism data determined that drotaverine gets adequately absorbed in the small intestine. On validating this finding in humans,it was observed that the half-life of absorption was 12 minutes after oral dosing. The drug not only exhibited quick absorption, but also showed maximum plasma concentrations within 45 minutes. About 65% of the dose remains unchanged in the systemic circulation.22Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent. JAMA India.2001;4(12):55-6.   It is considered to regulate the smooth muscle relaxation of the GIT and displays efficacy against spastic and motility disorders of the smooth muscle.23Misra SC, Pandey RM. Efficacy of drotaverine in irritable bowel syndrome: a double blind, randomized, placebo-controlled clinical trial. The American Journal of Gastroenterology. 2000;95(9):2544.   24Pap A, Hamvas J, Filiczky I, Burai M, Szikszay E. Beneficial effect of drotaverine in irritabile bowel syndrome (IBS). Gastroenterology. 1998;114(Suppl 1):A818.  

As abdominal pain is the cardinal symptom of IBS,smooth muscle relaxants are beneficial. Drotaverine by its phosphodiesterase isoenzyme IV (PDE-4) inhibitory and Ca-calmodulin complex inhibitory activity, relaxes the smooth muscles of the gut and helps in relieving abdominal pain. Drotaverine has quick onset of action and it is free from anti-cholinergic side effects, as seen with drugs like hyoscine. Drotaverine directly normalizes the gut motility, hence it is effective for both diarrhea and constipation predominant IBS. It shows significant improvement in stool frequency, consistency, urgency,and flatulence. Drotaverine is well tolerated, provides global relief from abdominal pain, and is now marketed in more than 50 countries world wide.21Mishra SC, Gupta K, Chatterjee N. Drotaverine in irritable bowel syndrome: A clinical review. Gastroenterology Today. 2001 October- December;5(4):186-188.   25Data on file. Walter Bushnell.  

A randomized placebo-controlled study16Rai 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.   was conducted that evaluated the efficacy and tolerability of drotaverine hydrochloride (80 mg tablet, thrice a day) in 180 patients with IBS. A significant decrease was observed in both, the pain frequency and pain severity scores. At the end of 2nd, 3rd, and 4th weeks of treatment, reduction in pain frequency was observed in 22 (25.9%), 51 (60%), and 66 (77.7%) patients in the drotaverine group, in contrast to 8 (9.4%), 18 (21.2%), and 26 (30.6%) individuals in the placebo group (figure 1).Global relief in abdominal pain with drotaverine versus placebo was 85.9% vs 39.5% and 82.4% vs 36.5% as perceived by the patient and the clinician, respectively (figure 2). Moreover, as depicted in figure 3, drotaverine group (44.7% patients) showed marked improvement in the stool frequency as compared to the placebo group (15.3% patients). The drug was well tolerated without any substantial adverse effects. In a similar study,21 it was observed that frequency and severity of pain in individuals with IBS decreased significantly with the use of 80mg thrice daily drotaverine (31.4% and 71.4% of patients, at the end of 2nd and 4th week, respectively) as compared to placebo (figure 4). Additionally, drotaverine led to remarkable improvement in stool frequency and global abdominal pain relief (figure 5). Besides, authors also noted that long term use of drotaverine, especially in pain predominant patients with IBS was without any significant side effects.

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These outcomes were corroborated by another study performed by Misra and colleagues,23Misra SC, Pandey RM. Efficacy of drotaverine in irritable bowel syndrome: a double blind, randomized, placebo-controlled clinical trial. The American Journal of Gastroenterology. 2000;95(9):2544.   wherein a total of 70 patients with IBS were recruited. The subjects (aged between 18 and 60 years) were randomized to receive either drotaverine (80 mg thrice daily) or placebo over a 4-week treatment period followed by a 4-week follow up. It was observed that after 2 weeks, pain frequency decreased in 11 (31.4%) patients in the drotaverine group and 2 (5.7%) in the placebo group. Similarly, after 4 weeks of therapy, 25 (71.4%) patients in the drotaverine group experienced reduction in pain frequency, in comparison to 11 (31.4%) patients in the placebo group.Drotaverine, when compared to placebo, also showed global improvement in abdominal pain (74.2% vs 37.7%) and stool frequency (25.7% vs 2.8%) without any overall effect on bowel movements. In another comparative study24Pap A, Hamvas J, Filiczky I, Burai M, Szikszay E. Beneficial effect of drotaverine in irritabile bowel syndrome (IBS). Gastroenterology. 1998;114(Suppl 1):A818.   on IBS, drotaverine effectively reduced bloating and pain in 47% of patients in study group, in comparison to 3% in the placebo group (figure 6).

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A self-control study 26Jing S, Yaozong Y, Jun G, Yunsheng Y, Yongdong W, Feng J, Minhu C, Kaichun W, Hong F. Treatment of irritable bowel syndrome with drotaverine hydrochloride: A multicentre clinical trial. Journal of Gastroenterology. 2010;15(12):735-737.   suggested that drotaverine is effective in treating all subtypes of IBS. Nearly 217 patients with IBS were treated with drotaverine hydrochloride tablets 80 mg three times a day for 2 weeks, and were compared with those before treatment. A significant drop in the average weekly score for abdominal pain was observed (figure 7) with an overall efficacy rate of 77.9% (figure 8). The mean daily stool frequency also remarkably increased and decreased in the IBS-C and IBS-D group, respectively (figure 9 and 10). Moreover, stool form and feeling of incomplete defecation, straining and urgency improved in both the groups without any major side effects. In a study by Khalif and coworkers, 20Khalif IL, Quigley EM, Makarchuk PA, Golovenko OV, Podmarenkova LF, Dzhanayev YA. Interactions between symptoms and motor and visceral sensory responses of irritable bowel syndrome patients to spasmolytics (antispasmodics). J Gastrointestin Liver Dis. 2009 Mar;18(1):17-22.    it was demonstrated that drotaverine significantly augmented the rectal threshold for discomfort/pain among individuals with IBS with predominant diarrhea. Furthermore, drotaverine may be considered superior to other antispasmodics, such as hyoscyamine, dicyclomine, propantheline, and mebeverine, as these are associated with numerous anticholinergic side effects.16Rai 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.    Data also indicates that amelioration in abdominal pain with mebeverine is statistically insignificant.27Darvish-Damavandi M, Nikfar S, Abdollahi M. A systematic review of efficacy and tolerability of mebeverine in irritable bowel syndrome. World Journal of Gastroenterology : WJG. 2010;16(5):547-553.    In addition,unlike these conventional antispasmodics, the painrelieving effect of drotaverine does not mask the symptoms of “acute abdomen,” which makes it unique,and may have relevant application in practice to achieve a rapid diagnosis.25Data on file. Walter Bushnell.

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References

    1. Basandra S, Bajaj D. Epidemiology of Dyspepsia and Irritable Bowel Syndrome (IBS) in Medical Students of Northern India. Journal of Clinical and Diagnostic Research : JCDR. 2014;8(12):JC13-JC16.
    2. Makharia GK, Verma AK, Amarchand R, Goswami A, Singh P,Agnihotri A, Suhail F, Krishnan A. Prevalence of Irritable Bowel Syndrome: A Community Based Study From Northern India. Journal of Neurogastroenterology and Motility. 2011;17(1):82-87.
    3. Spiller R, Aziz Q, Creed F, A Emmanuel, L Houghton, P Hungin, R Jones, D Kumar, G Rubin, N Trudgill, and P Whorwell. Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut. 2007;56(12):1770-1798.
    4. Upadhyay R, Singh A. Irritable Bowel Syndrome: The Indian Scenario.Available from: http://citeseerx.ist.psu.edu/viewdoc/download?doi =10.1.1.671.361&rep=rep1&type=pdf. Accessed on: 28.4.16.
    5. Lacy BE, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therapeutic Advances in Gastroenterology.2009;2(4):221-238.
    6. El-Salhy M. Irritable bowel syndrome: Diagnosis and pathogenesis.World Journal of Gastroenterology : WJG. 2012;18(37):5151-5163.
    7. Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B,Corinaldesi R. New pathophysiological mechanisms in irritable bowel syndrome. Aliment Pharmacol Ther. 2004 Jul;20 Suppl 2:1-9.
    8. Camilleri M, Ford MJ. Review article: colonic sensorimotor physiology in health, and its alteration in constipation and diarrhoeal disorders.Aliment Pharmacol Ther. 1998 Apr;12(4):287-302.
    9. Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2001 Apr;280(4):G519-24.
    10. Lasser RB, Bond JH, Levitt MD. The role of intestinal gas in functional abdominal pain. N Engl J Med. 1975 Sep 11;293(11):524-6.
    11. Chua ASB. Prevalence of Irritable Bowel Syndrome in Northern India.Journal of Neurogastroenterology and Motility. 2011;17(1):6-8.
    12. Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis,treatment, and evidence-based medicine. World Journal of Gastroenterology : WJG. 2014;20(22):6759-6773.
    13. Yoon SL, Grundmann O, Koepp L, Farrell L. Management of irritable bowel syndrome (IBS) in adults: conventional and complementary/ alternative approaches. Altern Med Rev. 2011 Jun;16(2):134-51.
    14. Talley NJ. Irritable bowel syndrome. Internal medicine journal.2006;36(11):724-728.
    15. Sainsbury A, Ford AC. Treatment of irritable bowel syndrome:beyond fiber and antispasmodic agents. Therapeutic Advances in Gastroenterology. 2011;4(2):115-127.
    16. 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.
    17. National Collaborating Centre for Nursing and Supportive Care (UK).Irritable Bowel Syndrome in Adults: Diagnosis and Management of Irritable Bowel Syndrome in Primary Care [Internet]. London: Royal College of Nursing (UK); 2008 Feb. (NICE Clinical Guidelines, No.61.) 7, Diet and lifestyle. Available from: http://www.ncbi.nlm.nih.gov/books/NBK51960/. Accessed on: 30.4.16.
    18. Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis,treatment, and evidence-based medicine. World Journal of Gastroenterology : WJG. 2014;20(22):6759-6773.
    19. Occhipinti K, Smith JW. Irritable Bowel Syndrome: A Review and Update. Clinics in Colon and Rectal Surgery. 2012;25(1):46-52.
    20. Khalif IL, Quigley EM, Makarchuk PA, Golovenko OV, Podmarenkova LF, Dzhanayev YA. Interactions between symptoms and motor and visceral sensory responses of irritable bowel syndrome patients to spasmolytics (antispasmodics). J Gastrointestin Liver Dis. 2009 Mar;18(1):17-22.
    21. Mishra SC, Gupta K, Chatterjee N. Drotaverine in irritable bowel syndrome: A clinical review. Gastroenterology Today. 2001 October- December;5(4):186-188.
    22. Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent. JAMA India.2001;4(12):55-6.
    23. Misra SC, Pandey RM. Efficacy of drotaverine in irritable bowel syndrome: a double blind, randomized, placebo-controlled clinical trial. The American Journal of Gastroenterology. 2000;95(9):2544.
    24. Pap A, Hamvas J, Filiczky I, Burai M, Szikszay E. Beneficial effect of drotaverine in irritabile bowel syndrome (IBS). Gastroenterology. 1998;114(Suppl 1):A818.
    25. Data on file. Walter Bushnell.
    26. Jing S, Yaozong Y, Jun G, Yunsheng Y, Yongdong W, Feng J, Minhu C, Kaichun W, Hong F. Treatment of irritable bowel syndrome with drotaverine hydrochloride: A multicentre clinical trial. Journal of Gastroenterology. 2010;15(12):735-737.
    27. Darvish-Damavandi M, Nikfar S, Abdollahi M. A systematic review of efficacy and tolerability of mebeverine in irritable bowel syndrome. World Journal of Gastroenterology : WJG. 2010;16(5):547-553.
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