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Recurrent abdominal pain in children: Focus on current management strategies

Introduction

Abdominal pain is a highly prevalent disorder of pediatric age group. It greatly affects the child’s wellbeing and incurs increased costs from school absenteeism and substantial health-care resource utilization.11Berger MY, Gieteling MJ, Benninga MA. Chronic abdominal pain in children. BMJ : British Medical Journal. 2007;334(7601):997-1002.    In clinical practice, pain that exceeds 1 or 2 months in duration is almost always considered to be chronic abdominal pain.2No authors listed. Chronic Abdominal Pain in Children. Pediatrics. Mar 2005;115(3):812-815.    It is said to be recurrent (RAP) when the pain persists for a minimum of three months in the preceding period, occurring for at least three times, which are severe enough to cause an impact on the daily activities of the affected patients.3Quak SH. Recurrent abdominal pain in children: a clinical approach. Singapore Medical Journal. 2015;56(3):125-128.    With the introduction of the Rome III criteria, this criterion was redefined to symptoms’ duration of two months prior to diagnosis.4Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A, Walker LS. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006 Apr;130(5):1527-37.    Generally, determination of the pain progression from its time of onset until brought to the attention of a medical practitioner serves as diagnostic clues to the condition.5Sherman R. Abdominal Pain. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 86. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK412/.    Approximately 15% of school children experience weekly episodes of abdominal pain and only 8% seek medical care.6Brett T, Rowland M, Drumm B. An approach to functional abdominal pain in children and adolescents. The British Journal of General Practice. 2012;62(600):386-387.    A large number of cases with abdominal pain are attributable to either functional or organic underlying cause, which are linked with altered gut motility, visceral hypersensitivity, abnormal brain-gut interaction, psychosocial disturbance, and immune activation that possibly explain the symptoms.7Korterink JJ, Diederen K, Benninga MA, Tabbers MM. Epidemiology of Pediatric Functional Abdominal Pain Disorders: A Meta-Analysis. PLoS ONE. 2015;10(5):e0126982.    However, recognition of abdominal pain in pediatric patients is often challenging, especially in the preverbal children. Therefore, a detailed history should be taken to elicit the related information along with a careful physical examination that may assist in refining the differential diagnosis.8Marin JR, Alpern ER. Abdominal pain in children. Emerg Med Clin North Am. 2011 May;29(2):401-28, ix-x.

Causes of abdominal pain in children

Functional cause: Functional abdominal pain is the most common cause of chronic abdominal pain in children and adolescents.2No authors listed. Chronic Abdominal Pain in Children. Pediatrics. Mar 2005;115(3):812-815.    6Brett T, Rowland M, Drumm B. An approach to functional abdominal pain in children and adolescents. The British Journal of General Practice. 2012;62(600):386-387.    In a study by Spee et al,9Spee LAA, Lisman-Van Leeuwen Y, Benninga MA, Bierma-Zeinstra SMA, Berger MY. Prevalence, characteristics, and management of childhood functional abdominal pain in general practice. Scandinavian Journal of Primary Health Care. 2013;31(4):197-202.    in almost 90% of children presenting with abdominal pain, the general physicians suspected functional abdominal pain.9 Its diagnosis is concluded after a thorough distinction from anatomic, infectious, inflammatory, or metabolic causes of abdominal pain.2No authors listed. Chronic Abdominal Pain in Children. Pediatrics. Mar 2005;115(3):812-815.    6Brett T, Rowland M, Drumm B. An approach to functional abdominal pain in children and adolescents. The British Journal of General Practice. 2012;62(600):386-387.    In the absence of any objective evidence of an organic pathology, causative role of emotional stress, visceral hypersensitivity, and gastrointestinal motility disorders has stemmed up.10Devanarayana NM, Rajindrajith S, De Silva HJ. Recurrent abdominal pain in children. Indian Pediatr. 2009 May;46(5):389-99.    In regards to this, functional abdominal pain is ascribed to functional dyspepsia, irritable bowel syndrome, abdominal migraine, functional abdominal pain syndrome (Table 1), or a combination of these.2No authors listed. Chronic Abdominal Pain in Children. Pediatrics. Mar 2005;115(3):812-815.

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Organic cause: Organic causes of RAP include Helicobacter pylori infection, eosinophilic esophagitis and reflux esophagitis, carbohydrate intolerance, abdominal migraine, inflammatory bowel disease, and surgical interventions.3Quak SH. Recurrent abdominal pain in children: a clinical approach. Singapore Medical Journal. 2015;56(3):125-128.    Prevalence of organic diseases has been reported to vary within different settings, ranging from 5% in the general population to 40% in a pediatric gastroenterologist practice.1Berger MY, Gieteling MJ, Benninga MA. Chronic abdominal pain in children. BMJ : British Medical Journal. 2007;334(7601):997-1002.    Indian data on the same indicates that organic pathologies it afflicts about 40% children with recurrent abdominal pain.11Ganesh R, Arvind Kumar R, Suresh N, Sathiyasekeran M. Chronic abdominal pain in children. Natl Med J India. 2010 Mar-Apr;23(2):94-9.    El-Matary and coworkers,12El-Matary W, Spray C, Sandhu B. Irritable bowel syndrome: the commonest cause of recurrent abdominal pain in children. Eur J Pediatr. 2004 Oct;163(10):584-8.    in their study on 103 children with abdominal pain, reported that 30% had organic pathologies associated with nocturnal symptoms and abdominal tenderness. On the other hand, non-organic pain showed a relationship with periumbilical locality, pain alleviation on defecation, and low fibre diet.12El-Matary W, Spray C, Sandhu B. Irritable bowel syndrome: the commonest cause of recurrent abdominal pain in children. Eur J Pediatr. 2004 Oct;163(10):584-8.    Persisting abdominal pain put the affected children at high risk of developing irritable bowel syndrome, emotional symptoms, and psychiatric disorders later in life.1Berger MY, Gieteling MJ, Benninga MA. Chronic abdominal pain in children. BMJ : British Medical Journal. 2007;334(7601):997-1002.    This underpins the need for prompt diagnosis and institution of an appropriate therapeutic strategy to prevent the manifestation of complications.

Recurrent abdominal pain associated with lactose intolerance: Lactose intolerance plays a contributory role in recurrent abdominal pain in children. Studies have shown that abdominal pain in children due to lactose intolerance can be up to 25%.13Blumenthal I, Kelleher J, Littlewood JM. Recurrent abdominal pain and lactose intolerance in childhood. British Medical Journal (Clinical research ed). 1981;282(6281):2013-2014.    More than 1/3rd of Indians suffer from lactase deficiency. It is prevalent in all age groups and generally increases with age.14Di Stefano M, Veneto G, Malservisi S, Strocchi A, Corazza GR. Lactose malabsorption and intolerance in the elderly. Scand J Gastroenterol. 2001 Dec;36(12):1274-8.    15Data on File. Walter-Bushnell.

Management of abdominal pain

Clinicians encounter a number of difficulties in the management of children with abdominal pain. This is primarily due to ‘second-hand’ history of pain in young children, as it is the caregiver’s interpretation of the reaction by the child to some abdominal upset. Nonetheless, parents are at least able to provide useful leads to the etiology of abdominal pain in their children. Furthermore, examination of abdomen of young children with abdominal pain is no less challenging.3Quak SH. Recurrent abdominal pain in children: a clinical approach. Singapore Medical Journal. 2015;56(3):125-128.    In context to this, Ganesh et al11Ganesh R, Arvind Kumar R, Suresh N, Sathiyasekeran M. Chronic abdominal pain in children. Natl Med J India. 2010 Mar-Apr;23(2):94-9.    proposed a practical approach towards the management of chronic abdominal pain in children, the first step of which involves categorization of pain after a detailed history and a thorough physical examination. The pain is classified according to the site of pain (epigastric, periumbilical, or left lower quadrant), the chief symptom associated with pain (dyspepsia, isolated pain, or altered bowel habits), and suspected cause behind the pain (organic or functional) based on the pain characteristics, and presence or absence of alarm features (Box 1).1Berger MY, Gieteling MJ, Benninga MA. Chronic abdominal pain in children. BMJ : British Medical Journal. 2007;334(7601):997-1002.    11Ganesh R, Arvind Kumar R, Suresh N, Sathiyasekeran M. Chronic abdominal pain in children. Natl Med J India. 2010 Mar-Apr;23(2):94-9.    However, acute attacks of chronic, functional abdominal pain may occasionally be confused with acute organic condition and vice versa. Therefore, “red flags” in the history and physical examination must be sought and excluded (Box 2).3Quak SH. Recurrent abdominal pain in children: a clinical approach. Singapore Medical Journal. 2015;56(3):125-128.    16Bufler P, Gross M, Uhlig HH. Recurrent Abdominal Pain in Childhood. Deutsches Ärzteblatt International. 2011;108(17):295-304.

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The second step involves implementation of proper investigations, ranging from simple tests when functional pain is suspected (Level I) to more diagnostic techniques (Level Ia) if there are alarm signs and pain is apparently organic. In individuals with greater possibility of organic pain, invasive investigations such as gastrointestinal endoscopy (Level II) may be helpful. Level III investigations, which include electroencephalogram and workup for food allergy and porphyria, are generally reserved for a small proportion of children.11Ganesh R, Arvind Kumar R, Suresh N, Sathiyasekeran M. Chronic abdominal pain in children. Natl Med J India. 2010 Mar-Apr;23(2):94-9.    A management algorithm has been described in Figure 1.3Quak SH. Recurrent abdominal pain in children: a clinical approach. Singapore Medical Journal. 2015;56(3):125-128.    16Bufler P, Gross M, Uhlig HH. Recurrent Abdominal Pain in Childhood. Deutsches Ärzteblatt International. 2011;108(17):295-304.

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The third step comprises management of abdominal pain tailored to the needs of the child.11Ganesh R, Arvind Kumar R, Suresh N, Sathiyasekeran M. Chronic abdominal pain in children. Natl Med J India. 2010 Mar-Apr;23(2):94-9.    Although there is paucity of data regarding the safety and efficacy of therapeutic options in children, treatment should be individualized and selected on the basis of disorder’s symptoms’ severity, any comorbid psychological problem, and its effect on the child’s normal functioning.17Miranda A, Sood M. Treatment options for chronic abdominal pain in children and adolescents. Curr Treat Options Gastroenterol. 2006 Sep;9(5):409-15.    While targeting the underlying etiology remains the principle approach in the treatment of organic abdominal pain, the objective behind therapy in the functional cases is to alleviate pain symptoms and to assist the child return to activities of daily life.11Ganesh R, Arvind Kumar R, Suresh N, Sathiyasekeran M. Chronic abdominal pain in children. Natl Med J India. 2010 Mar-Apr;23(2):94-9.     17Miranda A, Sood M. Treatment options for chronic abdominal pain in children and adolescents. Curr Treat Options Gastroenterol. 2006 Sep;9(5):409-15.    The therapeutic strategies have been discussed under local remedies, diet modification, psychological interventions, and pharmacotherapy.

Local remedies: Many local remedies have been in use to relieve symptoms in children with recurrent abdominal pain; however, their efficacy is yet to be established. Peppermint oil has been considered as one such option that has shown symptom improvement in about 71% children with irritable bowel syndrome in contrast to 43% in the placebo group.10Devanarayana NM, Rajindrajith S, De Silva HJ. Recurrent abdominal pain in children. Indian Pediatr. 2009 May;46(5):389-99.    10Devanarayana NM, Rajindrajith S, De Silva HJ. Recurrent abdominal pain in children. Indian Pediatr. 2009 May;46(5):389-99.

Diet modification: Dietary interventions, which include fibre supplements, lactose free diets or lactobacillus supplementation, have been found effective in the management of abdominal pain, yet lack of high quality evidence.19Huertas-Ceballos AA, Logan S, Bennett C, Macarthur C. Dietary interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003019.    In a study,20Feldman W, McGrath P, Hodgson C, Ritter H, Shipman RT. The use of dietary fiber in the management of simple, childhood, idiopathic, recurrent, abdominal pain. Results in a prospective, double-blind, randomized, controlled trial. Am J Dis Child. 1985 Dec;139(12):1216-8.    a significant drop in the number of pain attacks (at least 50% fewer than placebo) was observed in children with recurrent abdominal pain who were given additional fiber in their diet.20Feldman W, McGrath P, Hodgson C, Ritter H, Shipman RT. The use of dietary fiber in the management of simple, childhood, idiopathic, recurrent, abdominal pain. Results in a prospective, double-blind, randomized, controlled trial. Am J Dis Child. 1985 Dec;139(12):1216-8.    Moreover, lactose elimination diet for 4 weeks in children with lactose malabsorptionassociated abdominal pain demonstrated total pain relief.21Liebman WM. Recurrent abdominal pain in children: lactose and sucrose intolerance, a prospective study. Pediatrics 1979;64:43-45.    Besides, probiotics that commonly contain Lactobacillus, bifidobacteria or other living microorganisms are also known to improve symptoms of irritable bowel syndrome by restoring the microbial balance in the gut, enhancing the gut mucosal integrity, or by altering the intestinal inflammatory response.22Chiou E, Nurko S. Management of functional abdominal pain and irritable bowel syndrome in children and adolescents. Expert review of gastroenterology & hepatology. 2010;4(3):293-304.

Cognitive-behavioral therapy: Various psychological interventions, such as cognitive-behavioral therapy (CBT), hypnosis, guided imagery, and progressive relaxation have been successful in reducing abdominal pain and in improving social functioning and school attendance in children with chronic abdominal pain.17Miranda A, Sood M. Treatment options for chronic abdominal pain in children and adolescents. Curr Treat Options Gastroenterol. 2006 Sep;9(5):409-15.    23Youssef NN, Rosh JR, Loughran M, Schuckalo SG, Cotter AN, Verga BG, Mones RL. Treatment of functional abdominal pain in childhood with cognitive behavioral strategies. J Pediatr Gastroenterol Nutr. 2004 Aug;39(2):192-6.    These therapies, particularly CBT facilitate effective coping in children and their parents and alter the environmental pain-reinforcing factors.24Chambers CT, Holly C, Eakins D. Cognitive-behavioural treatment of recurrent abdominal pain in children: A primer for paediatricians. Paediatrics & Child Health. 2004;9(10):705-708.   

Pharmacotherapy: Over the years, a wide range of therapies have been introduced and studied.22Chiou E, Nurko S. Management of functional abdominal pain and irritable bowel syndrome in children and adolescents. Expert review of gastroenterology & hepatology. 2010;4(3):293-304.    These include H(2) blockers, proton-pump inhibitors, tricyclic antidepressants, and various serotonergic drugs; only weak evidence exists regarding beneficial effects of these agents in providing relief from symptoms.17Miranda A, Sood M. Treatment options for chronic abdominal pain in children and adolescents. Curr Treat Options Gastroenterol. 2006 Sep;9(5):409-15.    Analgesics have been largely prescribed traditionally for pain relief; their use however is now discouraged.25Leung AKC. Acute abdominal pain in children. Am Fam Physician 2003;67:2321-6.    This is because the effects of these agents often mask the physical “acute abdomen”, thereby interfering with accurate and rapid evaluation and diagnosis.25Leung AKC. Acute abdominal pain in children. Am Fam Physician 2003;67:2321-6.    26Jones A, Ramakrishnan K. Analgesics In The Initial Management Of Acute Abdominal Pain. The Internet Journal of Emergency Medicine 2005;2(2):1-8.    Moreover, sedation caused by analgesics may also make the diagnostic evaluation of the central nervous system function difficult.26Jones A, Ramakrishnan K. Analgesics In The Initial Management Of Acute Abdominal Pain. The Internet Journal of Emergency Medicine 2005;2(2):1-8.

For more than past two decades, smooth muscle relaxants (commonly called antispasmodics) have been extensively used for the management of abdominal pain. Individuals receiving antispasmodic drugs (such as anticholinergics), particularly for symptoms associated with meals and tenesmus, have shown improvement.27Lacy BE, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therapeutic Advances in Gastroenterology. 2009;2(4):221-238.    However, dry mouth, constipation, urinary retention, bowel obstruction, blurred vision, decreased sweating, and other bothersome side effects caused by anticholinergics limit their long-term use.27Lieberman JA. Managing Anticholinergic Side Effects. Primary Care Companion to The Journal of Clinical Psychiatry. 2004;6(suppl 2):20-23.    This warrants the need for a benchmark pharmacological agent that does not mask the acute symptoms, does not interfere with the diagnosis, is free of side effects (so that it can be safely given to children), and is capable of managing the symptoms more effectively. Drotaverine, a tolerable oral spasmolytic agent, offers a great potential in management of abdominal pain.29Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent. JAMA India. 2001;4(12):59-66.

Drotaverine: An effective antispasmodic in the management of abdominal pain in children

Drotaverine is a synthetic isoquinoline derivative that confers a powerful spasmolytic action on smooth muscle cells. It selectively inhibits phosphodiesterase isoenzyme IV, which makes it a promising agent in spastic and motility disorders of the smooth muscle.30Misra 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.    Drotaverine has been shown to undergo excellent absorption in the small intestine in the preclinical pharmacokinetic and metabolism studies. Likewise, in humans, the half-life of absorption of oral drotaverine was 12 minutes with maximum plasma concentration appearing within 45 minutes. The pain began to subside within 5-6 minutes in cases of spastic pain induced by gastrointestinal ulcer; the complete effect was appraised within 12 minutes. About 65% of the dose reaches unchanged in the systemic circulation.29Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent. JAMA India. 2001;4(12):59-66.

In contrast to the conventional spasmolytics that are known for their ability to inhibit intestinal passage, preclinical studies have revealed that therapeutic concentrations of drotaverine does not imply any inhibitory effect on gastrointestinal motility. In fact, authors evaluating its efficacy in different gastrointestinal indications suggested 72-86% of patients reporting relief in pain. Drotaverine is even known for prolonged pain relief and maintenance of spasmolysis.29 This can be validated by a study31Efficacy and safety of drotaverine hydrochloride in children with recurrent abdominal pain: a randomized placebo controlled trial. Available at: http://iapindia. org/files/abstracts2014/Absctract%202014.pdf. Accessed on: 29-05-17.    conducted to evaluate the efficacy of drotaverine in children (aged between 4 years and 12 years) with recurrent abdominal pain. Drotaverine hydrochloride or placebo was prescribed thrice a day for four weeks. The findings revealed fewer number of episodes of abdominal pain (n = 9.3) and lesser chance of missing school during 4 weeks of drotaverine in comparison to placebo (n = 21.2) (Figure 2).31Efficacy and safety of drotaverine hydrochloride in children with recurrent abdominal pain: a randomized placebo controlled trial. Available at: http://iapindia. org/files/abstracts2014/Absctract%202014.pdf. Accessed on: 29-05-17.    Interestingly, the European report on the survey of all medicinal products for pediatric use stated that drotaverine is used commonly in preschool and school children.32Report on the survey of all paediatric uses of medicinal products in Europe. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Report/ 2011/01/WC500101006.pdf. Accessed on: 29-05-17.

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Drotaverine holds a relevant application in practice as it does not interfere with diagnosis formulation. This is essentially because its anti-spasmodic and pain-killing effect does not mask the symptoms of “acute abdomen”.29Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent. JAMA India. 2001;4(12):59-66.    Moreover, it is well tolerated, does not exhibit any morphine or dextropropoxyphene like effect (thereby, no addiction), and is free from anticholinergic-associated adverse reactions.15Data on File. Walter-Bushnell.    29Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent. JAMA India. 2001;4(12):59-66.    These characteristics of drotaverine facilitate its use in cases without finalized diagnosis or in the emergency situation, resulting in decreased pain and spasm. Its dosage and benefits in children with abdominal pain are listed in Table 2.15Data on File. Walter-Bushnell.

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Lactase supplements for lactose intolerance

Studies show that abdominal pain in children can also be due to lactose intolerance. Most children refuse to take milk due to discomfort like pain, bloating, nausea and diarrhea that occur post-milk ingestion or even on consumption of lactose containing products. In such cases, lactase supplements can be useful in the children, which can be taken with milk and other lactose containing products.15

Conclusion

Abdominal pain is one of the most common disorders of pediatric age group. It greatly affects the child’s wellbeing and adds to the burden of increased costs associated with school absenteeism and health-care resource utilization. A large number of cases with abdominal pain are attributable to either functional or organic underlying cause. This can be ruled out by following a practical approach comprising 3 basic steps- history and examination (seeking alarm features and red flags), appropriate investigations, and individualized treatment. Local remedies, modified diet, CBT, and pharmacotherapy have been used to manage abdominal pain in children. While a plethora of therapeutic agents are available, drotaverine, an antispasmodic, has shown promising results. It is a highly potent and tolerable spasmolytic agent, suited for oral administration, and capable of preventing or relieving smooth muscle spasm of various organs, including abdominal pain. Cases where recurrent abdominal pain in children is suspected due to lactose intolerance, lactase enzyme supplements can be helpful.

References

  1. Berger MY, Gieteling MJ, Benninga MA. Chronic abdominal pain in children. BMJ : British Medical Journal. 2007;334(7601):997-1002.
  2. No authors listed. Chronic Abdominal Pain in Children. Pediatrics. Mar 2005;115(3):812-815.
  3. Quak SH. Recurrent abdominal pain in children: a clinical approach. Singapore Medical Journal. 2015;56(3):125-128.
  4. Rasquin A, Di Lorenzo C, Forbes D, Guiraldes E, Hyams JS, Staiano A, Walker LS. Childhood functional gastrointestinal disorders: child/adolescent. Gastroenterology. 2006 Apr;130(5):1527-37.
  5. Sherman R. Abdominal Pain. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 86. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK412/.
  6. Brett T, Rowland M, Drumm B. An approach to functional abdominal pain in children and adolescents. The British Journal of General Practice. 2012;62(600):386-387.
  7. Korterink JJ, Diederen K, Benninga MA, Tabbers MM. Epidemiology of Pediatric Functional Abdominal Pain Disorders: A Meta-Analysis. PLoS ONE. 2015;10(5):e0126982.
  8. Marin JR, Alpern ER. Abdominal pain in children. Emerg Med Clin North Am. 2011 May;29(2):401-28, ix-x.
  9. Spee LAA, Lisman-Van Leeuwen Y, Benninga MA, Bierma-Zeinstra SMA, Berger MY. Prevalence, characteristics, and management of childhood functional abdominal pain in general practice. Scandinavian Journal of Primary Health Care. 2013;31(4):197-202.
  10. Devanarayana NM, Rajindrajith S, De Silva HJ. Recurrent abdominal pain in children. Indian Pediatr. 2009 May;46(5):389-99.
  11. Ganesh R, Arvind Kumar R, Suresh N, Sathiyasekeran M. Chronic abdominal pain in children. Natl Med J India. 2010 Mar-Apr;23(2):94-9.
  12. El-Matary W, Spray C, Sandhu B. Irritable bowel syndrome: the commonest cause of recurrent abdominal pain in children. Eur J Pediatr. 2004 Oct;163(10):584-8.
  13. Blumenthal I, Kelleher J, Littlewood JM. Recurrent abdominal pain and lactose intolerance in childhood. British Medical Journal (Clinical research ed). 1981;282(6281):2013-2014.
  14. Di Stefano M, Veneto G, Malservisi S, Strocchi A, Corazza GR. Lactose malabsorption and intolerance in the elderly. Scand J Gastroenterol. 2001 Dec;36(12):1274-8.
  15. Data on File. Walter-Bushnell.
  16. Bufler P, Gross M, Uhlig HH. Recurrent Abdominal Pain in Childhood. Deutsches Ärzteblatt International. 2011;108(17):295-304.
  17. Miranda A, Sood M. Treatment options for chronic abdominal pain in children and adolescents. Curr Treat Options Gastroenterol. 2006 Sep;9(5):409-15.
  18. Kline RM, Kline JJ, Di Palma J, Barbero GJ. Enteric-coated, pH-dependent peppermint oil capsules for the treatment of irritable bowel syndrome in children. J Pediatr. 2001 Jan;138(1):125-8.
  19. Huertas-Ceballos AA, Logan S, Bennett C, Macarthur C. Dietary interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003019.
  20. Feldman W, McGrath P, Hodgson C, Ritter H, Shipman RT. The use of dietary fiber in the management of simple, childhood, idiopathic, recurrent, abdominal pain. Results in a prospective, double-blind, randomized, controlled trial. Am J Dis Child. 1985 Dec;139(12):1216-8.
  21. Liebman WM. Recurrent abdominal pain in children: lactose and sucrose intolerance, a prospective study. Pediatrics 1979;64:43-45.
  22. Chiou E, Nurko S. Management of functional abdominal pain and irritable bowel syndrome in children and adolescents. Expert review of gastroenterology & hepatology. 2010;4(3):293-304.
  23. Youssef NN, Rosh JR, Loughran M, Schuckalo SG, Cotter AN, Verga BG, Mones RL. Treatment of functional abdominal pain in childhood with cognitive behavioral strategies. J Pediatr Gastroenterol Nutr. 2004 Aug;39(2):192-6.
  24. Chambers CT, Holly C, Eakins D. Cognitive-behavioural treatment of recurrent abdominal pain in children: A primer for paediatricians. Paediatrics & Child Health. 2004;9(10):705-708.
  25. Leung AKC. Acute abdominal pain in children. Am Fam Physician 2003;67:2321-6.
  26. Jones A, Ramakrishnan K. Analgesics In The Initial Management Of Acute Abdominal Pain. The Internet Journal of Emergency Medicine 2005;2(2):1-8.
  27. Lacy BE, Weiser K, De Lee R. The Treatment of Irritable Bowel Syndrome. Therapeutic Advances in Gastroenterology. 2009;2(4):221-238.
  28. Lieberman JA. Managing Anticholinergic Side Effects. Primary Care Companion to The Journal of Clinical Psychiatry. 2004;6(suppl 2):20-23.
  29. Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent. JAMA India. 2001;4(12):59-66.
  30. 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.
  31. Efficacy and safety of drotaverine hydrochloride in children with recurrent abdominal pain: a randomized placebo controlled trial. Available at: http://iapindia. org/files/abstracts2014/Absctract%202014.pdf. Accessed on: 29-05-17.
  32. Report on the survey of all paediatric uses of medicinal products in Europe. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Report/ 2011/01/WC500101006.pdf. Accessed on: 29-05-17.
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