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Bush Beats 2015 › Bush Beats Issue 11, 2015

APPRAISING THE ROLE OF DROTAVERINE IN ACUTE ABDOMEN

Acute abdomen: An insight

Acute abdominal pain is a commonly encountered condition in patients of all age groups, characterized by severe pain arising in the abdominal region. While in some patients, the condition is benign, self-limiting, a significant proportion may show life-threatening signs warranting emergency treatment.1-3Murata A, 1. Okamoto K, Mayumi T, Maramatsu K, Matsuda S. Age-related differences in outcomes and etiologies of acute abdominal pain based on a national administrative database. Tohoku J Exp Med. 2014;233(1):9-15.
Balachandran B, Singhi S, Lal S. Emergency management of acute abdomen in children. Indian J Pediatr. 2013;80(3):226-34.
Ragsdale L, Southerland L. Acute abdominal pain in the older adult. Emerg Med Clin North Am. 2011 May;29(2):429-48, x.  

Remarkable research in the past decades has revealed much to suggest a high burden of the disease in primary care practice as well as emergency departments.4Stone R. Acute abdominal pain. Lippincotts Prim Care Pract. 1998 Jul-Aug;2(4):341-57.   A retrospective study 5Langell JT, Mulvihill SJ. Gastrointestinal perforation and the acute abdomen. Med Clin North Am. 2008 May;92(3):599-625, viii-ix.   was conducted on North Indian patients to shed light on the incidence of acute appendicitis. The authors not only demonstrated a continuous increase in the incidence from 2003 to 2012, but also reported acute appendicitis to be the most common cause of acute abdomen requiring surgical intervention. Another Indian study2Balachandran B, Singhi S, Lal S. Emergency management of acute abdomen in children. Indian J Pediatr. 2013;80(3):226-34.   revealed that acute abdomen accounts for about 8% of all children attending the emergency department. Besides, Russo et al6Russo MW, Wei JT, Thiny MT, Gangarosa LM, Brown A, Ringel Y, Shaheen NJ, Sandler RS. Digestive and liver diseases statistics, 2004. Gastroenterology. 2004;126(5):1448-53.   have shown abdominal pain to be the leading outpatient gastrointestinal diagnosis, accounting for 5.2 million hospital visits every year.

Acute abdomen is marked by sudden onset of pain that lasts for less than 24 hours; this contrasts with chronic cases wherein a long-standing intermittent or continuous pain is observed.7Abdullah M, Firmansyah MA. Diagnostic approach and management of acute abdominal pain. Acta Med Indones. 2012 Oct;44(4):344-50.  , 8American Academy of Pediatrics Subcommittee on Chronic Abdominal Pain; North American Society for Pediatric Gastroenterology Hepatology, and Nutrition. Chronic abdominal pain in children. Pediatrics. 2005;115(3):e370-81.   Immediate onset pain may be a scenario of urgency in a considerable fraction of patients and require prompt clinical evaluation and treatment. It has been observed that when faced with a patient with acute abdomen, clinicians rely on a sound knowledge of the diverse etiological spectrum of the condition. Analysis based on the specific causes of acute abdomen is of great value, as it aids in laying a foundation for an appropriate diagnostic and therapeutic approach.

Etiology

The precise etiology of abdominal pain may sometimes be hard to assess due to the multitudinal pathophysiological factors underlying the disorder, and the variability in intensity and nature of pain across individuals. In broad terms, the etiological spectrum of the disorder encompasses acute surgical diseases, intra- and extra-abdominal disorders, systemic illnesses and, commonly, functional abdominal pain.10Yang W-C, Chen C-Y, Wu H-P. Etiology of non-traumatic acute abdomen in pediatric emergency departments. World Journal of Clinical Cases : WJCC. 2013;1(9):276-284.  , 11Boyd CA, Riall TS. Unexpected Gynecological Findings during Abdominal Surgery. Current Problems in Surgery. 2012;49(4):195-251.   While a diverse range of specific causes have also been explored, a few among them such as appendicitis, biliary colic, cholecystitis, diverticulitis, bowel obstruction, visceral perforation, pancreatitis, peritonitis and renal colic rank among the most common.7Abdullah M, Firmansyah MA. Diagnostic approach and management of acute abdominal pain. Acta Med Indones. 2012 Oct;44(4):344-50.  , 10Yang W-C, Chen C-Y, Wu H-P. Etiology of non-traumatic acute abdomen in pediatric emergency departments. World Journal of Clinical Cases : WJCC. 2013;1(9):276-284.   Agboola and coworkers9 undertook a comparative analysis of the specific etiologies of acute abdomen in adult patients at a surgical emergency unit. The results revealed that the commonest cause of acute abdomen was appendicitis (30.3%) followed by intestinal obstruction (27.9%), perforated typhoid ileitis 14.9% and peptic ulcer disease (7.6%) (figure 1). In contrast with these results, Murata et al1 demonstrated intestinal infection to be the most frequent etiology of acute abdominal pain, followed by ileus, peritonitis, cholelithiasis and diverticulitis (figure 2).

Besides, hepatoma necrosis, splenic and myocardial infarction, diabetic ketoacidosis, and sigmoid, cecum or stomach volvulus account for the

Figure 1 Common causes of acute abdomen in adult patients
Figure 1: Common causes of acute abdomen in adult patients at a surgical emergency unit9
Figure 2 Common causes of acute abdomen in a hospital
Figure 2: Common causes of acute abdomen in a hospital-based population1

less frequently encountered etiologies.7Abdullah M, Firmansyah MA. Diagnostic approach and management of acute abdominal pain. Acta Med Indones. 2012 Oct;44(4):344-50.   Researchers have also identified a myriad of gastrointestinal and genitourinary disorders responsible for acute abdomen in the pediatric population; some of these are enlisted in box 1.12Leung AK, Sigalet DL. Acute abdominal pain in children. Am Fam Physician. 2003 Jun 1;67(11):2321-6.  

The site and character of pain also aid in predicting the cause of acute abdomen. A comparative description of the common causes, location and nature of pain is presented in table 1.

Pathophysiology

Abdominal pain is divided into visceral, parietal, and referred pain depending upon the type of the receptors involved. It is worthy of note that the stimulation

Box 1: Causes of acute abdominal pain in children
  • Acute cholecystitis.
  • Acute appendicitis or Meckel’s diverticulitis.
  • Acute pancreatitis.
  • Constipation
  • Inflammatory bowel disease
  • Lactose intolerance
  • Peptic ulcer disease.
  • Intestinal obstruction
  • Gastroenteritis
  • Renal colic
  • Acute urinary retention.
  • Abdominal trauma
Adapted from: Leung AK, Sigalet DL. Acute abdominal pain in children. Am Fam Physician. 2003 Jun 1;67(11):2321-6.

 

Table 1: Comparison of common causes, location and character of acute abdominal pain
Causes Site Character
Appendicitis Periumbilical early; right lower quadrant late Ache
Cholecystitis Right upper quadrant Constricting
Pancreatitis Epigastric, back Blunt
Diverticulitis Left lower quadrant Ache
Perforated peptic ulcer Epigastric Burning sensation
Small bowel obstruction Periumbilical Cramping
Adapted from: Abdullah M, Firmansyah MA. Diagnostic approach and management of acute abdominal pain. Acta Med Indones. 2012 Oct;44(4):344-50.

of visceral nociceptors is the key event in inducing abdominal pain. Visceral nociception is transmitted by unmyelinated-C nerve fibers located on the serosal surface, periosteum, mesentery, peritoneum and mucosa of hollow organs. Since these fibres enter the spinal cord bilaterally at different levels, pain is perceived in the midline (epigastrium, periumbilical or hypogastrium) and is interpreted as dull, cramping, and poorly localized.

Parietal pain, in contrast, is usually transmitted by myelinated A-δ fibers, present in the parietal peritoneum, skin and muscle. Most of the nociception conveyed by these fibers is interpreted as sharp, immediate-onset and well-localized, mimicking the pain that follows an acute event. Parietal peritoneum, when irritated, is sensitive to movement, coughing and vibration.

Referred pain shares several features of parietal pain, but is perceived at distant sites supplied by the same dermatome as the affected abdominal organ. It is a result of convergence of visceral and parietal afferent neurons from various regions on secondorder neurons in the spinal cord at the same spinal segment. For example, inflammatory disease of the diaphragm due to splenic rupture or subphrenic hematoma can be felt as pain in the shoulder or lower neck region.7Abdullah M, Firmansyah MA. Diagnostic approach and management of acute abdominal pain. Acta Med Indones. 2012 Oct;44(4):344-50.  ,12Leung AK, Sigalet DL. Acute abdominal pain in children. Am Fam Physician. 2003 Jun 1;67(11):2321-6.  ,13Kim JS. Acute Abdominal Pain in Children. Pediatric Gastroenterology, Hepatology & Nutrition. 2013;16(4):219-224.  

Diagnostic approach and clinical evaluation

Patients presenting to healthcare facilities with acute abdominal pain can be challenging to diagnose. Notwithstanding the dramatic presentation of the disease, up to 40% of the affected patients do not receive a definitive diagnosis on the first evaluation, either due to initial stage of the illness or subtle/atypical signs. Besides, the vast spectrum of differential diagnosis further complicates the investigative strategy (figure 3). Acute abdominal pain warrants an early and accurate diagnosis so that subsequent treatment can be speedily instituted. A meticulous history, wellfocused physical examination, together with the use of laboratory and imaging studies constitute the best method of evaluation.7Abdullah M, Firmansyah MA. Diagnostic approach and management of acute abdominal pain. Acta Med Indones. 2012 Oct;44(4):344-50.  , 14Stone R, Primary care diagnosis of acute abdominal pain. Nurse Pract. 1996 Dec;21(12 Pt 1):19-20, 23-30, 35-9; quiz 40-1.  –16Panebianco NL, Jahnes K, Mills AM. Imaging and laboratory testing in acute abdominal pain. Emerg Med Clin North Am. 2011 May;29(2):175-93, vii.   Obtaining a history of prior abdominal surgery or medical conditions that cause acute abdominal pain, such as diabetic ketoacidosis and hypercalcemia can rule out certain conditions and aid in simplifying diagnosis. Other important historical variables include symptom onset pattern, progression, site, intensity and aggravating/relieving factors of pain.

Abdominal physical examination also provides key assistance in establishing the diagnosis. The pelvic organs and external genitalia must be thoroughly examined to ascertain the degree of abdominal tenderness, rigidity and distension. Besides, specific laboratory studies substantially help in assessing the patient’s physiological status and formulate the diagnosis.

Imaging

While undoubtedly, medical history, physical examination, and clinical tests are crucial aspects of the diagnostic workup, several authors have demonstrated that an evaluation based solely on

Figure 3 Differential diagnosis of abdominal pain
Figure 3: Differential diagnosis of abdominal pain according to pain location
Drotaverine is a selective PDE IV inhibitor which does not mask the symptoms of acute abdomen or interfere with diagnostic precision while providing optimum pain control

these measures may not be sufficiently reliable. Imaging has been shown to have a positive effect on the accuracy of the clinical diagnosis, increase the degree of diagnostic certainity and assist in decision making. Traditionally, imaging modalities have been limited to the use of plain abdominal radiographs; however, whether they contribute to therapeutic decision-making or disposition remains questionable. Hence, advanced imaging with ultrasonography and computed tomography (CT) has garnered considerable attention, particularly in patients requiring emergency medical care. CT is a valuable investigative tool as it facilitates an accurate and reproducible diagnosis in urgent scenarios. During the last decade, a trend towards increased use of CT in patients with abdominal pain has been witnessed. The use of early CT has been shown to significantly reduce the number of misdiagnosed cases. It is additionally cost effective and thereby recommended by researchers as the primary technique for diagnosing all acute abdominal pain cases, except those with clinically suspected acute cholecystitis. For these patients, ultrasonography abdomen should be the preferred technique. Ultrasonography is employed as one of the most initial investigations in almost all cases with moderate and severe pain with localized abdominal findings. In patients with extensive abdominal trauma or signs of pancreatitis, a Contrast Enhanced Computerized Tomography (CECT) abdomen is the imaging modality of choice.7Abdullah M, Firmansyah MA. Diagnostic approach and management of acute abdominal pain. Acta Med Indones. 2012 Oct;44(4):344-50.  ,13Kim JS. Acute Abdominal Pain in Children. Pediatric Gastroenterology, Hepatology & Nutrition. 2013;16(4):219-224.  ,17Stoker J, van Randen A, Lameris W, Boermeester MA. Imaging patients with acute abdominal pain. Radiology. 2009 Oct;253(1):31-46.  –20Lameris W, 20. van Randen A, van Es HW. Imaging strategies for detection of urgent conditions in patients with acute abdominal pain: diagnostic accuracy study. BMJ : British Medical Journal. 2009;338:b2431.  

Management

A myriad of researchers and clinicians have pursued individual approaches to improve treatment outcomes in patients with acute abdomen. Investigators opine that patient education directed towards an explanation of the pathophysiology of the disease is a prerequisite step which provides the rationale for the introduction of interventions. The interventional spectrum encompasses general measures, pharmacotherapy and psychological interventions. In some cases, surgical exploration may be indicated, depending on each patient’s clinical signs and response to medical therapy.21Farmer AD, Aziz Q. Mechanisms and management of functional abdominal pain. J R Soc Med. 2014 Sep;107(9):347-54.  ,22Mazzaferro EM. Triage and approach to the acute abdomen. Clin Tech Small Anim Pract. 2003 Feb;18(1):1-6.  

In patients with acute abdomen, painful symptoms can be severe enough to affect the day-to-day activity which makes immediate symptom alleviation necessary. For achieving prompt relief of abdominal pain, antispasmodics are used in the emergency (until the door of the hospital) and thereafter the underlying cause can be identified using rapid diagnostic procedures. Unlike what was previously believed, administration of antispasmodic drugs does not alter physicians’ ability to accurately evaluate and treat the patients, and therefore should not be withheld until diagnosis has been established. Drotaverine is a selective PDE IV inhibitor which does not mask the symptoms of acute abdomen or interfere with diagnostic precision while providing optimum pain control. It also displays a favorable safety profile, unlike other anticholinergic antispasmodics (such as dicyclomine) which are associated with a range of adverse effects (Box 2).

A large body of data shows drotaverine to be a highly potent spasmolytic agent which is effective

Box 2: Benefits of drotaverine
  • Site specific action: acts directly on abdominal smooth muscles
  • Effectively maintains a state of spasmolysis
  • Safe in frequent & repetitive dosing (wide therapeutic window)
  • Safe in pregnancy, hypertension, glaucoma, elderly, and patients suffering from GERD
  • Negligible drug-drug interactions
  • Available as combination with aceclofenac, mefenamic acid & paracetamol
  • Well tolerated across all age groups
  • Does not induce anticholinergic adverse effects such as constipation, urinary retention, dry mouth and visual disturbances, commonly seen with the use of hyoscyamine and dicyclomine.
  • Does not mask the symptoms of acute abdomen, and interfere with diagnosis and further treatment modalities
Adapted from: 1. Darvish-Damavandi M, Nikfar S, Abdollahi M. A systematic review of efficacy and tolerability of mebeverine in irritable bowel syndrome. World J Gastroenterol. 2010 Feb 7;16(5):547-53. 2. 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. 3. Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent: drotaverine. J Am Med Assoc Ind. 1998;1:63-9. 4. Golzari SE, Soleimanpour H, Rahmani F. Therapeutic Approaches for Renal Colic in the Emergency Department: A Review Article. Anesthesiology and Pain Medicine. 2014;4(1):e16222.
Figure 4 Patients showing symptom relief while
Figure 4: Patients showing symptom relief while in transit to hospital on treatment with drotaverine

either alone or in combination with other analgesics, in antagonizing spasmodic pain originating from various organs. The drug also demonstrates its suitability for both oral and parenteral administration.23Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent: drotaverine. J Am Med Assoc Ind. 1998;1:63-9.  

Place of drotaverine in therapy

Due to its strong antispasmodic effect, drotaverine is extensively employed in biliary, intestinal and renal colic, for labor augmentation, dysmenorrhea and prior to instrumental investigative procedures. It does not have morphine-like effect and therefore does not induce addictive potential.24Sharma JB, Aruna J, Kumar P, Roy KK, Malhotra N, Kumar S. Comparison of efficacy of oral drotaverine plus mefenamic acid with paracervical block and with intravenous sedation for pain relief during hysteroscopy and endometrial biopsy. Indian J Med Sci. 2009;63:244-52.  –26Vanuytsel T, Tack JF, Boeckxstaens GE. Treatment of abdominal pain in irritable bowel syndrome. J Gastroenterol. 2014 Aug;49(8):1193-205.  

Investigators have garnered a great deal of evidence to demonstrate the efficacy and tolerability of drotaverine in patients with acute abdomen. Romics et al27Romics I, Molnar DL, Timberg G, Mrklic B, Jelakovic B, Koszegi G, Blasko G. The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int. 2003 Jul;92(1):92-6.   undertook a trial to assess the spasmolytic effect of drotaverine in acute colicky pain caused by renal and ureteric stones. The results revealed that drotaverine was effective in abolishing or significantly reducing acute colicky pain.

Biochemical studies on drotaverine have also shown that its two metabolites in bile (a deoxy-, and a deoxy-desethyl, metabolite) are ten times more active in inhibiting PDE IV than drotaverine, which could be the basis of the successful treatments observed in patients presenting with acute abdominal pain due to biliary spasm disorders.

Drotaverine has also found an important place in emergency medicine. Its versatile pharmacokinetic properties such as fast absorption, immediate onset of action, rapid response to IV dosing and wide therapeutic window favorably contribute to its utility in emergency conditions. The Hungarian Ambulance Service (HAS) undertook a retrospective evaluation of patients (with severe acute pain) while in transit to the hospital, and assessed the effect of drotaverine in this setting. The results showed complete pain relief in more than 80% and partial relief in 12% of the patients (figure 4). These findings were taken a step further in another study by HAS which evaluated 5934 patients with acute abdomen of gastrointestinal, urological, biliary, gynecological and other origins. During the time of transit to hospital, drotaverine was promptly administered and the results were analyzed. Drotaverine treatment was considered very effective

Figure 5 Efficacy and tolerability of emergency
Figure 5: Efficacy and tolerability of emergency administration of drotaverine in patients with acute abdomen during transit to hospital

and partly effective in 61.2% and 31% of the patients, respectively. The absence of adverse events in majority (95.8%) of the patients throughout this time period was a noteworthy finding of the study (figure 5).23Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent: drotaverine. J Am Med Assoc Ind. 1998;1:63-9.  

Based on the aforementioned clinical evidences, a strong case can be made for the prompt administration of drotaverine in emergency cases of acute abdomen.

Conclusion

Acute abdominal pain is recurrently encountered in outpatient settings and emergency departments. It has a broad and often confusing differential diagnosis. Physicians seeking to treat the condition must have an in-depth knowledge of the mechanisms of abdominal pain, as well as the common gastrointestinal causes that carry potentially higher morbidity and mortality. There is incontrovertible evidence that prompt and adequate pain relief for patients with acute abdominal pain is humane, does not adversely affect diagnostic acumen or clinical decision making, and must be considered absolutely essential during the initial management of each patient. The use of selective PDE IV inhibitors such as drotaverine appears to be more advisable, as it does not hinder diagnosis or interfere with treatment modalities in the affected patients. There is compelling evidence derived from a plethora of studies demonstrating the efficacy and safety of drotaverine in the treatment of acute abdomen. It effectively maintains a state of spasmolysis, is well-tolerated across all age groups and fairs better over its competitor drugs in terms of tolerability profile.

References

  1. Murata A, Okamoto K, Mayumi T, Maramatsu K, Matsuda S. Age-related differences in outcomes and etiologies of acute abdominal pain based on a national administrative database. Tohoku J Exp Med. 2014;233(1):9-15.
  2. Balachandran B, Singhi S, Lal S. Emergency management of acute abdomen in children. Indian J Pediatr. 2013;80(3):226-34.
  3. Ragsdale L, Southerland L. Acute abdominal pain in the older adult. Emerg Med Clin North Am. 2011 May;29(2):429-48, x.
  4. Stone R. Acute abdominal pain. Lippincotts Prim Care Pract. 1998 Jul-Aug;2(4):341-57.
  5. Langell JT, Mulvihill SJ. Gastrointestinal perforation and the acute abdomen. Med Clin North Am. 2008 May;92(3):599-625, viii-ix.
  6. Russo MW, Wei JT, Thiny MT, Gangarosa LM, Brown A, Ringel Y, Shaheen NJ, Sandler RS. Digestive and liver diseases statistics, 2004. Gastroenterology. 2004;126(5):1448-53.
  7. Abdullah M, Firmansyah MA. Diagnostic approach and management of acute abdominal pain. Acta Med Indones. 2012 Oct;44(4):344-50.
  8. American Academy of Pediatrics Subcommittee on Chronic Abdominal Pain; North American Society for Pediatric Gastroenterology Hepatology, and Nutrition. Chronic abdominal pain in children. Pediatrics. 2005;115(3):e370-81.
  9. Agboola JO, Olatoke SA, Rahman GA. Pattern and presentation of acute abdomen in a Nigerian teaching hospital. Nigerian Medical Journal : Journal of the Nigeria Medical Association. 2014;55(3):266-270.
  10. Yang W-C, Chen C-Y, Wu H-P. Etiology of non-traumatic acute abdomen in pediatric emergency departments. World Journal of Clinical Cases : WJCC. 2013;1(9):276-284.
  11. Boyd CA, Riall TS. Unexpected Gynecological Findings during Abdominal Surgery. Current Problems in Surgery. 2012;49(4):195-251.
  12. Leung AK, Sigalet DL. Acute abdominal pain in children. Am Fam Physician. 2003 Jun 1;67(11):2321-6.
  13. Kim JS. Acute Abdominal Pain in Children. Pediatric Gastroenterology, Hepatology & Nutrition. 2013;16(4):219-224.
  14. Stone R, Primary care diagnosis of acute abdominal pain. Nurse Pract. 1996 Dec;21(12 Pt 1):19-20, 23-30, 35-9; quiz 40-1.
  15. Macaluso CR, McNamara RM. Evaluation and management of acute abdominal pain in the emergency department. International Journal of General Medicine. 2012;5:789-797.
  16. Panebianco NL, Jahnes K, Mills AM. Imaging and laboratory testing in acute abdominal pain. Emerg Med Clin North Am. 2011 May;29(2):175-93, vii.
  17. Stoker J, van Randen A, Lameris W, Boermeester MA. Imaging patients with acute abdominal pain. Radiology. 2009 Oct;253(1):31-46.
  18. Lameris W, van Randen A, Dijkgraaf MG, Bossuyt PM, Stoker J, Boermeester MA. Optimization of diagnostic imaging use in patients with acute abdominal pain (OPTIMA): Design and rationale. BMC Emergency Medicine. 2007;7:9.
  19. Gans SL, Stoker J, Boermeester MA. Plain abdominal radiography in acute abdominal pain; past, present, and future. International Journal of General Medicine. 2012;5:525-533.
  20. Lameris W, 20. van Randen A, van Es HW. Imaging strategies for detection of urgent conditions in patients with acute abdominal pain: diagnostic accuracy study. BMJ : British Medical Journal. 2009;338:b2431.
  21. Farmer AD, Aziz Q. Mechanisms and management of functional abdominal pain. J R Soc Med. 2014 Sep;107(9):347-54.
  22. Mazzaferro EM. Triage and approach to the acute abdomen. Clin Tech Small Anim Pract. 2003 Feb;18(1):1-6.
  23. Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent: drotaverine. J Am Med Assoc Ind. 1998;1:63-9.
  24. Sharma JB, Aruna J, Kumar P, Roy KK, Malhotra N, Kumar S. Comparison of efficacy of oral drotaverine plus mefenamic acid with paracervical block and with intravenous sedation for pain relief during hysteroscopy and endometrial biopsy. Indian J Med Sci. 2009;63:244-52.
  25. 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.
  26. Vanuytsel T, Tack JF, Boeckxstaens GE. Treatment of abdominal pain in irritable bowel syndrome. J Gastroenterol. 2014 Aug;49(8):1193-205.
  27. Romics I, Molnar DL, Timberg G, Mrklic B, Jelakovic B, Koszegi G, Blasko G. The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int. 2003 Jul;92(1):92-6.
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