Irritable Bowel Syndrome: An Overview and the Role of Drotaverine

Introduction

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder, characterized by recurrent abdominal pain, cramping, bloating, constipation and diarrhea, in the absence of detectable structural abnormalities. Although it causes a lot of discomfort and distress, it does not permanently harm the intestines and has no serious complications, such as cancer. IBS can be usually controlled with diet, stress management and prescribed medications, but sometimes may be disabling enough to prevent sufferers from working, attending social events or even travelling short distances.¹Irritable bowel syndrome. Available at http://digestive.niddk.nih.gov/ddiseases/pubs/ibs/. Accessed on June 27, 2011.

Epidemiology

The prevalence of IBS varies by country and by age range examined. The disease is more common in women than in men in most parts of the world. In the Indian subcontinent, however, the trend is reversed, with men constituting almost 70-80% of patients with IBS.²Lehrer JK. Irritable Bowel Syndrome. Available at http://emedicine.medscape.com/article/180389-overview#showall. Accessed on June 27, 2011. According to a report of the Indian Society of Gastroenterology Task Force, symptoms suggestive of IBS were present in 4.2% of the Indian population.³Ghoshal UC, Abraham P, Bhatt C, 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 Jan-Feb;27(1):22-8.

Most people seeking medical attention for IBS symptoms for the first time are in the age group of 30-50 years. The prevalence of IBS declines after the age of 60. In fact, it is rare to find IBS occurring after the age of 40, unless it is caused by infection, medication, trauma or cholecystectomy.⁴Frissora CL. Diagnosis, Treatment, and Management of Irritable Bowel Syndrome with Constipation and Chronic Constipation. Available at http://www.medscape.org/viewarticle/509930_2. Accessed on July 07, 2011.

Pathophysiology

The pathophysiology of IBS is poorly understood, but altered GI motility, visceral hyperalgesia, psychological disturbances and stress have been proposed as playing a role.

Altered GI motility

The myoelectric activity of the colon is composed of background slow waves with superimposed spike potentials. Colonic dysmotility in irritable bowel syndrome causes variations in slow-wave frequency and a blunted, late-peaking, postprandial response of spike potentials. This disparity is observed more in patients who are prone to diarrhea than in those who are prone to constipation.

Due to small bowel dysmotility, meal transit is delayed in patients prone to constipation and accelerated in patients prone to diarrhea. In addition, there are shorter intervals between migratory motor complexes (the predominant interdigestive small bowel motor patterns).

The overall result of these widespread motility aberrations is a generalized smooth muscle hyperresponsiveness, manifesting as increased urinary symptoms, including frequency, urgency, nocturia, and hyperresponsiveness to methacholine challenge.²Lehrer JK. Irritable Bowel Syndrome. Available at http://emedicine.medscape.com/article/180389-overview#showall. Accessed on June 27, 2011.

Serotonin signaling

Serotonin (5-hydroxytryptamine; 5-HT) is a biogenic amine that functions as a neurotransmitter of sensorimotor function in the gastrointestinal tract. It plays a crucial role in the initiation of motility and secretory reflexes, in enteric neurotransmission, and in signaling to the central nervous system.⁵Brandt LJ. On the Relationship between Colon Ischemia, Irritable Bowel Syndrome, and Serotonergic Therapy of Irritable Bowel Syndrome. Available at http://www.medscape.org/viewarticle/488174_4. Accessed on July 07, 2011.

The 5HT-containing enterochromaffin cells in the colon are increased in diarrhea-predominant IBS patients compared to healthy subjects or to patients with ulcerative colitis. In addition, postprandial plasma 5HT plasma levels are significantly higher in diarrhea-predominant IBS patients compared to healthy controls. The increased release of 5HT may contribute to the postprandial symptoms of these patients and provides a rationale for the use of 5HT antagonists in the treatment of this disorder.⁶Harrison’s Principles of Internal Medicine, 16th ed.

Visceral hyperalgesia

Visceral hyperalgesia refers to enhanced perception of normal motility and visceral pain. IBS patients frequently exhibit exaggerated sensory responses to visceral stimulation. Postprandial pain has been temporally related to the entry of the food bolus into the cecum in 74% of patients. Rectal balloon inflation produces nonpainful and painful sensations at lower volumes in IBS patients than in healthy controls without altering rectal tension, suggestive of visceral afferent dysfunction in IBS.⁶Harrison’s Principles of Internal Medicine, 16th ed.  It should be noted that hypersensitivity occurs with rapid but not with gradual distension.

As a result of visceral hyperalgesia, the dermatomal distribution of referred pain gets widened. Sensitization of the intestinal afferent nociceptive pathways that synapse in the dorsal horn of the spinal cord provides a unifying mechanism.²Lehrer JK. Irritable Bowel Syndrome. Available at http://emedicine.medscape.com/article/180389-overview#showall. Accessed on June 27, 2011.

Psychopathology

Many of IBS patients display abnormal psychiatric features. Visceral distension leads to exaggerated symptoms in most of these patients, even after ruling out psychological factors.⁶Harrison’s Principles of Internal Medicine, 16th ed. Patients with psychological disturbances report more frequent and debilitating illness than control populations. Patients who seek medical care have a higher incidence of panic disorder, major depression, anxiety disorder, and hypochondriasis than control populations.²Lehrer JK. Irritable Bowel Syndrome. Available at http://emedicine.medscape.com/article/180389-overview#showall. Accessed on June 27, 2011.  Psychological factors also influence pain thresholds in IBS patients; stress alters sensory thresholds. An association between prior sexual or physical abuse and development of IBS has been reported.⁶Harrison’s Principles of Internal Medicine, 16th ed.

Patients with irritable bowel syndrome may also have suicidal ideation and/or suicide attempts strictly as a result of their bowel symptoms.⁷Miller V’ Hopkins L, Whorwell PJ. Suicidal ideation in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. Dec 2004;2(12):1064-8.

Microscopic inflammation

Hitherto, it was believed that IBS does not cause any demonstrable pathological changes. But recently, evidence of microscopic inflammation – both in the colon and the small bowel – has been found in some patients with IBS, as well as in those with a preceding history of infectious enteritis (postinfectious irritable bowel syndrome). Risk factors predisposing to postinfectious irritable bowel syndrome include longer duration of illness, the type of pathogen involved, smoking, female gender, an absence of vomiting during the infectious illness, and young age.⁸Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology. May 2009; 136(6): 1979-88.

Laparoscopic full-thickness jejunal biopsy samples revealed infiltration of lymphocytes into the myenteric plexus and intraepithelial lymphocytes⁹Törnblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology. Dec 2002;123(6):1972-9. and neuronal degeneration of the myenteric plexus. In postinfectious irritable bowel syndrome, there may be increased numbers of colonic mucosal lymphocytes and enteroendocrine cells. The latter secrete high levels of serotonin, increasing colonic secretion and possibly leading to diarrhea.

Symptoms of bloating and distention in IBS can be attributed to bacterial overgrowth in the small bowel. In addition, the patterns and contents of gut bacteria may be altered in IBS patients vis-à-vis controls.¹⁰Kassinen A, Krogius-Kurikka L, Mäkivuokko H, Rinttilä T, Paulin L, Corander J, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. Jul 2007;133(1):24-33.

Imbalanced gut flora

The human gut flora comprises several bacteria that are important for the maintenance of good health. It has been claimed that quantitative and/or qualitative changes in intestinal flora may contribute to sensorymotor dysfunction of IBS. This may occur through increased fermentation of food with gas production, bile acid malabsorption and mucosal irritation and minimal inflammation.¹¹Barbara G, De Giorgio R, Stanghellini V, et al. New pathophysiological mechanisms in irritable bowel syndrome. Alimentary Pharmacology & Therapeutics 2004;20(s2):1-9.

Food sensitivities/intolerances

Most patients with IBS have unidentified food sensitivities or intolerances. Some of the most common food triggers are wheat, gluten, dairy, corn, sugar, chocolate, coffee, tea and citrus fruits. They can be identified by the use of sensitive allergy antibody tests and an elimination diet. Once discovered, elimination of the offending food(s) from the diet will ameliorate the symptoms of IBS.¹²Pick M. Irritable bowel syndrome – is it all in your head? Available at http://www.womentowomen.com/digestionandgihealth/ ibs.aspx. Accessed on July 07, 2011.

Hormonal imbalance

In some women, IBS symptoms worsen just before their periods. While the exact reason is not clear, the pattern of hormonal fluctuation in the second half of the cycle may be responsible. In this phase, estrogen is lower for several days, whereas progesterone is relatively high at the end of the cycle, and then declines suddenly just before the period. Progesterone, in general, slows gut motility, and subnormal estrogen levels have been detected in women with IBS. An imbalance between these two hormones may lead to sluggish bowel movement. which, in turn, could aggravate pelvic congestion, cramping, and abdominal distension.¹²Pick M. Irritable bowel syndrome – is it all in your head? Available at http://www.womentowomen.com/digestionandgihealth/ ibs.aspx. Accessed on July 07, 2011.

Environmental factors

Some common medical conditions, including IBS, may be related to environmental factors, like stress and anxiety. Of the various substances that are released during the stress response, one that appears to have major significance in the stress response is corticotropin-releasing-factor (CRF), which is found in both the brain and the gut. In the brain, CRF receptors are found in the areas related to digestion, emotions and the autonomic nervous system. In the gut, CRF increases mucus and water secretion, affects colonic motility and may also cause abdominal pain.¹³Monnikes, H, et al. Role of stress in functional gastrointestinal disorders. Evidence for stress-induced alterations in gastrointestinal motility and sensitivity. Digestive Diseases 2001 19:201-211.

Genetic factors

A genetic component in IBS is suggested by data that show (i) clustering of IBS in families; (ii) 2-fold increased frequency of IBS in monozygotic twins compared with dyzigotic twins; (iii) polymorphism of genes controlling down-regulation of inflammation (i.e., IL-10 and transforming growth factor-β1) and serotonin re-uptake transporter (SERT). It has been suggested that genetic factors interact most probably with environmental factors for the full phenotypic expression of the disease. Further studies are needed to clarify the involvement of genetic factors in IBS.¹¹Barbara G, De Giorgio R, Stanghellini V, et al. New pathophysiological mechanisms in irritable bowel syndrome. Alimentary Pharmacology & Therapeutics 2004;20(s2):1-9.

Clinical presentation

The clinical picture of IBS consists of the following symptoms:⁶Harrison’s Principles of Internal Medicine, 16th ed.

• Abdominal pain, which is recurrent and accompanied with cramps
• Altered bowel habit – constipation or diarrhea
• Abdominal distension with increased amount of bloating and gas
• Upper GI symptoms, like dyspepsia, heartburn, nausea, and vomiting

Diagnosis

The Rome III criteria system was developed to classify the functional gastrointestinal disorders based on clinical symptoms. Each disorder has its own set of criteria. The Rome III criteria for IBS are as follows:

Symptoms of recurrent abdominal pain or discomfort and a marked change in bowel habit for at least six months, with symptoms experienced on at least three days of at least three months. Two or more of the following conditions must be present:

• Pain is relieved by a bowel movement
• Onset of pain is related to a change in the frequency of stool
• Onset of pain is related to a change in the form or appearance of stool

Supporting symptoms include the following:

• Altered stool frequency
• Altered stool form
• Altered stool passage (straining and/or urgency)
• Mucorrhea
• Abdominal bloating or subjective distention

Four bowel patterns may be seen with irritable bowel syndrome, viz.:

• IBS-D (diarrhea predominant)
• IBS-C (constipation predominant)
• IBS-M (mixed diarrhea and constipation)
• IBS-A (alternating diarrhea and constipation)

It has been seen that within 1 year, 75% of patients change subtypes, and 29% switch between constipation-predominant IBS and diarrhea-predominant IBS.¹⁴Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. Apr 2006;130(5):1480-91.

Complications

The complications of IBS are:¹⁵Irritable bowel syndrome. Available at http://www.mayoclinic.com/health/irritable-bowel-syndrome/DS00106/DSECTION=complications. Accessed on July 07, 2011.

• Aggravation of hemorrhoids due to diarrhea and constipation
• Malnourishment if certain foods are avoided as the symptoms are often related to eating
• Impaired quality of life due to the psychosocial effects of the disease, such as avoiding social engagements, not being able to enjoy a healthy sex life, not being able to reach one’s professional potential, etc. These effects may lead to discouragement or even depression.

Approach to treatment

The management of IBS is aimed at controlling the predominant symptoms, i.e., abdominal pain, bloating, constipation and diarrhea. It consists of dietary modifications, psychotherapy and pharmacotherapy.

Dietary modifications

Dietary measures that can help in IBS are:²Lehrer JK. Irritable Bowel Syndrome. Available at http://emedicine.medscape.com/article/180389-overview#showall. Accessed on June 27, 2011.

• Fiber supplementation for constipation and diarrhea. In some patients, high-fiber diets may aggravate bloating and distension. In general, polycarbophil compounds may produce less flatulence than psyllium compounds.
• Judicious water intake for constipation.
• Avoidance of caffeine to reduce anxiety and symptom exacerbation.
• Avoidance of legumes to decrease abdominal bloating.
• Avoidance or limited intake of lactose and/or fructose if they are a contributory factor. Calcium supplements should be given if lactose intake is restricted.

Psychological therapy

Psychological therapy should be provided by a professional in the field. According to the 2009 position statement of the American College of Gastroenterology (ACG), psychological interventions, cognitive behavioral therapy, dynamic psychotherapy, and hypnotherapy, are more effective than placebo.²Lehrer JK. Irritable Bowel Syndrome. Available at http://emedicine.medscape.com/article/180389-overview#showall. Accessed on June 27, 2011.

Pharmacotherapy

Pharmacotherapy in IBS is directed at the symptoms. A list of drugs used for management of symptoms is given in Table 1.²Lehrer JK. Irritable Bowel Syndrome. Available at http://emedicine.medscape.com/article/180389-overview#showall. Accessed on June 27, 2011.

Rationale for using antispasmodics in IBS

Smooth muscle spasm is believed to play a fundamental role in the pathophysiology of pain in IBS.¹⁶Quigley EM. Disturbances of motility and visceral hypersensitivity in irritable bowel syndrome: biological markers or epiphenomenon. Gastroenterol Clin North Am 2005;34:221-233.   Since the underlying problem in IBS involves excess contraction of smooth muscle in the gut wall, the use of antispasmodics is of paramount importance.¹⁷Khalif IL, Quigley EM, et al. Interactions between symptoms and motor and visceral sensory response of irritable bowel syndrome patients to spasmolytics (antispasmodics). J Gastrointestin Liver Dis. 2009 March;18(1):17-22.   The use of anticholinergic antispasmodics, i.e., dicyclomine, hyoscine, clidinium bromide, etc. is limited by their anticholinergic side effects that include dry mouth, heat prostration, constipation, obstructive organopathies, etc.¹⁸Anticholinergic (Oral Route, Parenteral Route, Rectal Route, Transdermal Route). Available at http://www.mayoclinic.com/health/drug-information/DR602315/DSECTION=side-effects. Accessed on August 23, 2011.   In addition to anticholinergic side effects, clidinium bromide has CNS side effects that may produce drowsiness or blurred vision.¹⁹Anticholinergics/Antispasmodics (Systemic). Available at http://www.drugs.com/mmx/clidinium-bromide.html. Accessed on August 23, 2011.   Drotaverine is a musculotropic antispasmodic agent that relaxes the smooth muscle in the gut and is devoid of anticholinergic side effects.²⁰Mishra SC, Gupta K, Chatterjee N. Drotaverine in irritable bowel syndrome: A clinical review. Gastroenterology Today. 2001 OctoberDecember;5(4):186-188.

Role of drotaverine in IBS

Drotaverine is an antispasmodic drug, structurally related to papaverine. It is a selective inhibitor of the enzyme phosphodiesterase IV (which plays a regulatory role in smooth muscle relaxation of the gastrointestinal tract), and has no anticholinergic effects.²¹Drotaverine. Available at http://en.wikipedia.org/wiki/Drotaverine. Accessed on June 27, 2011.

Drotaverine has been found to be useful in spastic and motility disorders of the smooth muscle. Some smooth-muscle relaxants have been shown to cause 27% and 19% improvements over placebo in global assessment and pain, respectively.²²Pap A, Hamvas J et al. Beneficial effect of drotaverine in irritable bowel syndrome (IBS). Gastroenterology 1998; 114(Suppl 1):A818.

A crossover study²³Bolaji OO, Onyeji CO, Ogundaini AO, Olugbade TA, Ogunbona FA. Pharmacokinetics and bioavailability of drotaverine in humans. Eur J Drug Metab Pharmacokinet. 1996 Jul-Sep;21(3):217-21.   investigated the pharmacokinetics and bioavailability of drotaverine in 10 healthy volunteers, who were administered a single dose of 80 mg orally and intravenously. It was found that pharmacokinetic parameters, such as elimination half-life, plasma clearance, renal clearance and apparent volume of distribution, were not influenced by the route of drug administration. The drug was mainly eliminated by non-renal routes since renal clearance accounted for only 0.31 ± 0.13% of the total plasma clearance. The absolute bioavailability was variable and ranged from 24.5-91% with a mean of 58.2 ± 18.2% (mean ± SD).

Abdominal pain and bowel disturbance are the most distressing symptoms of IBS. The efficacy of drotaverine in relieving these symptoms was evaluated by Misra and colleagues²⁴Misra SC, Pandey RM. Efficacy of drotaverine in irritable bowel syndrome: a double blind, randomized, placebo-controlled clinical trial. The American Journal of Gastroenterology 2000;95:2544.   in a prospective double blind, randomized placebo-controlled study. For this purpose, they recruited 70 consecutive patients of IBS (Rome criteria) aged between 18 and 60 years, who 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. The scores of abdominal pain and bowel habits were recorded at entry and further assessed at weekly intervals. Relief in frequency and severity of abdominal pain, improvement in bowel habit and global efficacy of drug treatment were taken as endpoints.

The following results were obtained (Fig. 1):

• At 2 weeks, pain frequency decreased in 11 (31.4%) patients in the drotaverine group and 2 (5.7%) in the placebo group.
• At 4 weeks, pain frequency decreased in 25 (71.4%) patients, in the drotaverine group and 11 (31.4%) patients in the placebo group.
• Pain severity scores decreased significantly in the drotaverine group 25 (71.4%), as compared with placebo 11 (31.4%) at 4 weeks.
• The global relief in abdominal pain, as perceived by the patient and the clinician, was significantly greater with drotaverine (74.2%) than with placebo (37.7%).
• Improvement in stool frequency was greater in the drotaverine group (25.7%) in comparison to placebo group (2.8%).

Drotaverine was thus shown to produce global improvement in abdominal pain in irritable bowel syndrome without any overall effect on bowel movements.

Another double blind, randomized, placebo control study¹⁷Khalif IL, Quigley EM, et al. Interactions between symptoms and motor and visceral sensory response of irritable bowel syndrome patients to spasmolytics (antispasmodics). J Gastrointestin Liver Dis. 2009 March;18(1):17-22.    enrolled 62 patients (53 females, 9 males, mean age 50.8 ± 14.2 years) with IBS and constipation and, after a 2-week pretreatment period, assigned them to either 3×2 tablets (3×80 mg) of drotaverine (n=30) or 3×2 tablets of placebo (n=32) for 8 weeks. Fourteen patients dropped from the study at least partially. Abdominal pain, stool frequency, bloating or distention and dyspepsia were recorded and scored. Colon transit time was also measured with radioopaque markers before and at the end of treatment.

Results were as under:

• The severity of abdominal pain was significantly reduced by 47% with drotaverine, whereas it actually increased by 3% with placebo.
• Bloating was somewhat, but not significantly, decreased by drotaverine but dyspepsia and constipation did not change.
• According to the opinion of the patients and physicians, drotaverine was effective in 15/24 (60%) and 17/24 (68%) cases, respectively.
• No significant adverse effect was observed during the treatment period.

The above results led the investigators to conclude that drotaverine can effectively diminish abdominal pain and bloating in IBS.

Conclusion

Irritable bowel syndrome (IBS) refers to a disorder that involves abdominal pain and cramping, as well as changes in bowel movements. Treatment involves psychotherapy and dietary modifications, with pharmacological agents playing an adjuvant role for symptomatic relief. Drotaverine, a smooth muscle relaxant, has been found to be quite effective in alleviating the symptoms of IBS.

References

1. Irritable bowel syndrome. Available at http://digestive.niddk.nih.gov/ddiseases/pubs/ibs/. Accessed on June 27, 2011.
2. Lehrer JK. Irritable Bowel Syndrome. Available at http://emedicine.medscape.com/article/180389-overview#showall. Accessed on June 27, 2011.
3. Ghoshal UC, Abraham P, Bhatt C, 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 Jan-Feb;27(1):22-8.
4. Frissora CL. Diagnosis, Treatment, and Management of Irritable Bowel Syndrome with Constipation and Chronic Constipation. Available at http://www.medscape.org/viewarticle/509930_2. Accessed on July 07, 2011.
5. Brandt LJ. On the Relationship between Colon Ischemia, Irritable Bowel Syndrome, and Serotonergic Therapy of Irritable Bowel Syndrome. Available at http://www.medscape.org/viewarticle/488174_4. Accessed on July 07, 2011.
6. Harrison’s Principles of Internal Medicine, 16th ed.
7. Miller V’ Hopkins L, Whorwell PJ. Suicidal ideation in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. Dec 2004;2(12):1064-8.
8. Spiller R, Garsed K. Postinfectious irritable bowel syndrome. Gastroenterology. May 2009; 136(6): 1979-88.
9. Törnblom H, Lindberg G, Nyberg B, Veress B. Full-thickness biopsy of the jejunum reveals inflammation and enteric neuropathy in irritable bowel syndrome. Gastroenterology. Dec 2002;123(6):1972-9.
10. Kassinen A, Krogius-Kurikka L, Mäkivuokko H, Rinttilä T, Paulin L, Corander J, et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology. Jul 2007;133(1):24-33.
11. Barbara G, De Giorgio R, Stanghellini V, et al. New pathophysiological mechanisms in irritable bowel syndrome. Alimentary Pharmacology & Therapeutics 2004;20(s2):1-9.
12. Pick M. Irritable bowel syndrome – is it all in your head? Available at http://www.womentowomen.com/digestionandgihealth/ ibs.aspx. Accessed on July 07, 2011.
13. Monnikes, H, et al. Role of stress in functional gastrointestinal disorders. Evidence for stress-induced alterations in gastrointestinal motility and sensitivity. Digestive Diseases 2001 19:201-211.
14. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology. Apr 2006;130(5):1480-91.
15. Irritable bowel syndrome. Available at http://www.mayoclinic.com/health/irritable-bowel-syndrome/DS00106/DSECTION=complications. Accessed on July 07, 2011.
16. Quigley EM. Disturbances of motility and visceral hypersensitivity in irritable bowel syndrome: biological markers or epiphenomenon. Gastroenterol Clin North Am 2005;34:221-233.
17. Khalif IL, Quigley EM, et al. Interactions between symptoms and motor and visceral sensory response of irritable bowel syndrome patients to spasmolytics (antispasmodics). J Gastrointestin Liver Dis. 2009 March;18(1):17-22.
18. Anticholinergic (Oral Route, Parenteral Route, Rectal Route, Transdermal Route). Available at http://www.mayoclinic.com/health/drug-information/DR602315/DSECTION=side-effects. Accessed on August 23, 2011.
19. Anticholinergics/Antispasmodics (Systemic). Available at http://www.drugs.com/mmx/clidinium-bromide.html. Accessed on August 23, 2011.
20. Mishra SC, Gupta K, Chatterjee N. Drotaverine in irritable bowel syndrome: A clinical review. Gastroenterology Today. 2001 OctoberDecember;5(4):186-188.
21. Drotaverine. Available at http://en.wikipedia.org/wiki/Drotaverine. Accessed on June 27, 2011.
22. Pap A, Hamvas J et al. Beneficial effect of drotaverine in irritable bowel syndrome (IBS). Gastroenterology 1998; 114(Suppl 1):A818.
23. Bolaji OO, Onyeji CO, Ogundaini AO, Olugbade TA, Ogunbona FA. Pharmacokinetics and bioavailability of drotaverine in humans. Eur J Drug Metab Pharmacokinet. 1996 Jul-Sep;21(3):217-21.
24. 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;95:2544.