Korean J Gastroenterol.  2024 May;83(5):184-190. 10.4166/kjg.2024.045.

Pharmacologic Treatment of Chronic Constipation

• Wang H
• Lee JW

• KMID: 2555970
• DOI: http://doi.org/10.4166/kjg.2024.045

Abstract

Chronic constipation is a common disease that can impair the quality of life, with a prevalence of 14% globally and 16.5% in South Korea. Straining, hard stools, the sensation of incomplete evacuation, the sensation of anorectal blockage, and manual maneuvers to facilitate defecation are the related symptoms of chronic constipation. On the other hand, medications commonly referred to as laxatives are the essentials of treatment for constipation compared to non-pharmacological treatment, such as lifestyle modifications, biofeedback, or surgery. Unfortunately, there is still an unmet need to determine if pharmacological treatment for constipation is being administered appropriately. Therefore, there are many disadvantages as to whether the indications and side effects of laxatives are adequately considered and prescribed as the primary treatment modality for constipation in a real clinical situation in Korea. Laxatives are generally recommended as the next step for patients in whom organic causes have been excluded and have not responded to initial non-pharmacologic therapies such as dietary fiber intake and exercise. Laxatives can be classified as bulk-forming laxatives, osmotic laxatives, stimulant laxatives, and other novel laxatives. On the other hand, there are distinct mechanisms underlying constipation, and appropriate administration is the most decisive. Therefore, the present investigators prepared this review to discuss appropriate pharmacological strategies for chronic constipation in Korea. Moreover, this paper also includes suggestions for appropriate pharmacological treatment options for special patient populations.

Keyword

Constipation; Treatment; Laxatives

Reference

1. Mearin F, Lacy BE, Chang L, et al. 2016; Bowel disorders. Gastroenterology. 150:1393–1407.e5. DOI: 10.1053/j.gastro.2016.02.031. PMID: 27144627.

2. Suares NC, Ford AC. 2011; Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol. 106:1582–1591. quiz 15811592DOI: 10.1038/ajg.2011.164. PMID: 21606976.

3. Jun DW, Park HY, Lee OY, et al. 2006; A population-based study on bowel habits in a Korean community: prevalence of functional constipation and self-reported constipation. Dig Dis Sci. 51:1471–1477. DOI: 10.1007/s10620-006-9087-3. PMID: 16832618.

4. Cho YS, Lee YJ, Shin JE, et al. 2023; 2022 Seoul consensus on clinical practice guidelines for functional constipation. J Neurogastroenterol Motil. 29:271–305. DOI: 10.5056/jnm23066. PMID: 37417257. PMCID: PMC10334201.

5. Mori H, Tack J, Suzuki H. 2021; Magnesium oxide in constipation. Nutrients. 13:421. DOI: 10.3390/nu13020421. PMID: 33525523. PMCID: PMC7911806.

6. Mori H, Suzuki H, Hirai Y, et al. 2019; Clinical features of hypermagnesemia in patients with functional constipation taking daily magnesium oxide. J Clin Biochem Nutr. 65:76–81. DOI: 10.3164/jcbn.18-117. PMID: 31379418. PMCID: PMC6667383.

7. Ferdinandus J, Pederson JA, Whang R. 1981; Hypermagnesemia as a cause of refractory hypotension, respiratory depression, and coma. Arch Intern Med. 141:669–670. DOI: 10.1001/archinte.1981.00340050115027. PMID: 7224750.

8. Collins EN, Russell PW. 1949; Fatal magnesium poisoning following magnesium sulfate, glycerin, and water enema in primary megacolon. Cleve Clin Q. 16:162–166. DOI: 10.3949/ccjm.16.3.162. PMID: 18132462.

9. Obokhare I. 2012; Fecal impaction: a cause for concern? Clin Colon Rectal Surg. 25:53–58. DOI: 10.1055/s-0032-1301760. PMID: 23449376. PMCID: PMC3348734.

10. Zhao Q, Chen YY, Xu DQ, et al. 2021; Action mode of gut motility, fluid and electrolyte transport in chronic constipation. Front Pharmacol. 12:630249. DOI: 10.3389/fphar.2021.630249. PMID: 34385914. PMCID: PMC8353128.

11. Lee-Robichaud H, Thomas K, Morgan J, Nelson RL. Lactulose versus polyethylene glycol for chronic constipation. Cochrane Database Syst Rev. 2010; (7):CD007570. DOI: 10.1002/14651858.CD007570.pub2. PMID: 20614462.

12. Dipalma JA, Cleveland MV, McGowan J, Herrera JL. 2007; A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol. 102:1436–1441. DOI: 10.1111/j.1572-0241.2007.01199.x. PMID: 17403074.

13. Di Palma JA, Cleveland MV, McGowan J, Herrera JL. 2007; An open-label study of chronic polyethylene glycol laxative use in chronic constipation. Aliment Pharmacol Ther. 25:703–708. DOI: 10.1111/j.1365-2036.2006.03228.x. PMID: 17311603.

14. Brigstocke S, Yu V, Nee J. 2022; Review of the safety profiles of laxatives in pregnant women. J Clin Gastroenterol. 56:197–203. DOI: 10.1097/MCG.0000000000001660. PMID: 35050942.

15. Rao SSC, Qureshi WA, Yan Y, Johnson DA. 2022; Constipation, hemorrhoids, and anorectal disorders in pregnancy. Am J Gastroenterol. 117(10S):16–25. DOI: 10.14309/ajg.0000000000001962. PMID: 36194029.

16. Li H, Zhang P, Xue Y. 2020; A comparison of the safety and efficacy of polyethylene glycol 4000 and lactulose for the treatment of constipation in pregnant women: a randomized controlled clinical study. Ann Palliat Med. 9:3785–3792. DOI: 10.21037/apm-20-1674. PMID: 33302648.

17. Fleming V, Wade WE. 2010; A review of laxative therapies for treatment of chronic constipation in older adults. Am J Geriatr Pharmacother. 8:514–550. DOI: 10.1016/S1543-5946(10)80003-0. PMID: 21356503.

18. Lederle FA, Busch DL, Mattox KM, West MJ, Aske DM. 1990; Cost-effective treatment of constipation in the elderly: a randomized double-blind comparison of sorbitol and lactulose. Am J Med. 89:597–601. DOI: 10.1016/0002-9343(90)90177-F. PMID: 2122724.

19. Kasugai K, Iwai H, Kuboyama N, Yoshikawa A, Fukudo S. 2019; Efficacy and safety of a crystalline lactulose preparation (SK-1202) in Japanese patients with chronic constipation: a randomized, double-blind, placebo-controlled, dose-finding study. J Gastroenterol. 54:530–540. DOI: 10.1007/s00535-018-01545-7. PMID: 30643982. PMCID: PMC6536483.

20. Chassagne P, Ducrotte P, Garnier P, Mathiex-Fortunet H. 2017; Tolerance and long-term efficacy of polyethylene glycol 4000 (Forlax®) compared to lactulose in elderly patients with chronic constipation. J Nutr Health Aging. 21:429–439. DOI: 10.1007/s12603-016-0762-6. PMID: 28346570.

21. Zhou Y, Yang X, Fan L, et al. 2015; Observations on the curative effect of lactulose for postpartum constipation based on a large sample study. Int J Clin Exp Med. 8:19167–19171.

22. Tayebi-Khosroshahi H, Habibzadeh A, Niknafs B, et al. 2016; The effect of lactulose supplementation on fecal microflora of patients with chronic kidney disease; a randomized clinical trial. J Renal Inj Prev. 5:162–167. DOI: 10.15171/jrip.2016.34. PMID: 27689115. PMCID: PMC5040005.

23. Lin CJ, Pan CF, Ju SY, et al. 2016; Assessment of the pharmacokinetics, removal rate of hemodialysis, and safety of lactulose in hemodialysis patients. J Food Drug Anal. 24:876–880. DOI: 10.1016/j.jfda.2016.05.007. PMID: 28911627. PMCID: PMC9337276.

24. Bharucha AE, Lacy BE. 2020; Mechanisms, evaluation, and management of chronic constipation. Gastroenterology. 158:1232–1249. e3. DOI: 10.1053/j.gastro.2019.12.034. PMID: 31945360. PMCID: PMC7573977.

25. Krueger D, Demir IE, Ceyhan GO, Zeller F, Schemann M. 2018; bis-(p-hydroxyphenyl)-pyridyl-2-methane (BHPM)-the active metabolite of the laxatives bisacodyl and sodium picosulfate-enhances contractility and secretion in human intestine in vitro. Neurogastroenterol Motil. 30:e13311. DOI: 10.1111/nmo.13311. PMID: 29441646.

26. Mascolo N, Capasso R, Capasso F. 1998; Senna. A safe and effective drug. Phytotherapy Research. 12(S1):S143–S145. DOI: 10.1002/(SICI)1099-1573(1998)12:1+<S143::AID-PTR277>3.0.CO;2-G.

27. Noergaard M, Traerup Andersen J, Jimenez-Solem E, Bring Christensen M. 2019; Long term treatment with stimulant laxatives -clinical evidence for effectiveness and safety? Scand J Gastroenterol. 54:27–34. DOI: 10.1080/00365521.2018.1563806. PMID: 30700194.

28. Morishita D, Tomita T, Mori S, et al. 2021; Senna versus magnesium oxide for the treatment of chronic constipation: A randomized, placebo-controlled trial. Am J Gastroenterol. 116:152–161. DOI: 10.14309/ajg.0000000000000942. PMID: 32969946.

29. Elran-Barak R, Goldschmidt AB, Crow SJ, et al. 2017; Is laxative misuse associated with binge eating? Examination of laxative misuse among individuals seeking treatment for eating disorders. Int J Eat Disord. 50:1114–1118. DOI: 10.1002/eat.22745. PMID: 28766762. PMCID: PMC5861734.

30. Joo JS, Ehrenpreis ED, Gonzalez L, et al. 1998; Alterations in colonic anatomy induced by chronic stimulant laxatives: the cathartic colon revisited. J Clin Gastroenterol. 26:283–286. DOI: 10.1097/00004836-199806000-00014. PMID: 9649012.

31. Morales MA, Hernández D, Bustamante S, Bachiller I, Rojas A. 2009; Is senna laxative use associated to cathartic colon, genotoxicity, or carcinogenicity? J Toxicol. 2009:287247. DOI: 10.1155/2009/287247. PMID: 20107583. PMCID: PMC2809429.

32. Chmielewska A, Szajewska H. 2010; Systematic review of randomised controlled trials: probiotics for functional constipation. World J Gastroenterol. 16:69–75.

33. Besselink MG, van Santvoort HC, Buskens E, et al. 2008; Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet. 371:651–659. DOI: 10.1016/S0140-6736(08)60207-X. PMID: 18279948.

34. Camilleri M, Deiteren A. 2010; Prucalopride for constipation. Expert Opin Pharmacother. 11:451–461. DOI: 10.1517/14656560903567057. PMID: 20102308.

35. Tack J, van Outryve M, Beyens G, Kerstens R, Vandeplassche L. 2009; Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives. Gut. 58:357–365. DOI: 10.1136/gut.2008.162404. PMID: 18987031.

36. Gilsenan A, Fortuny J, Cainzos-Achirica M, et al. 2019; Cardiovascular safety of prucalopride in patients with chronic constipation: A multinational population-based cohort study. Drug Saf. 42:1179–1190. DOI: 10.1007/s40264-019-00835-0. PMID: 31134512. PMCID: PMC6739451.

37. Smith WB, Mannaert E, Verhaeghe T, Kerstens R, Vandeplassche L, Van de Velde V. 2012; Effect of renal impairment on the pharmacokinetics of prucalopride: a single- dose open-label Phase I study. Drug Des Devel Ther. 6:407–415. DOI: 10.2147/DDDT.S36142. PMID: 23269861. PMCID: PMC3529624.

38. Lacy BE, Levy LC. 2007; Lubiprostone: a chloride channel activator. J Clin Gastroenterol. 41:345–351. DOI: 10.1097/01.mcg.0000225665.68920.df. PMID: 17413599.

39. Tuteja AK, Rao SS. 2008; Lubiprostone for constipation and irritable bowel syndrome with constipation. Expert Rev Gastroenterol Hepatol. 2:727–733. DOI: 10.1586/17474124.2.6.727. PMID: 19090733.

40. Lembo AJ, Johanson JF, Parkman HP, Rao SS, Miner PB Jr, Ueno R. 2011; Long-term safety and effectiveness of lubiprostone, a chloride channel (ClC-2) activator, in patients with chronic idiopathic constipation. Dig Dis Sci. 56:2639–2645. DOI: 10.1007/s10620-011-1801-0. PMID: 21769655. PMCID: PMC3169778.

41. Rao SSC, Lichtlen P, Habibi S. 2021; Effects of lubiprostone, an intestinal secretagogue, on electrolyte homeostasis in chronic idiopathic and opioid-induced constipation. J Clin Gastroenterol. 55:512–519. DOI: 10.1097/MCG.0000000000001385. PMID: 32569031. PMCID: PMC8183482.

42. Lembo AJ, Schneier HA, Shiff SJ, et al. 2011; Two randomized trials of linaclotide for chronic constipation. N Engl J Med. 365:527–536. DOI: 10.1056/NEJMoa1010863. PMID: 21830967.

43. Lacy BE, Schey R, Shiff SJ, et al. 2015; Linaclotide in chronic idiopathic constipation patients with moderate to severe abdominal bloating: A randomized, controlled trial. PLoS One. 10:e0134349. DOI: 10.1371/journal.pone.0134349. PMID: 26222318. PMCID: PMC4519259.

44. Schoenfeld P, Lacy BE, Chey WD, et al. 2018; Low-dose linaclotide (72 μg) for chronic idiopathic constipation: A 12-week, randomized, double-blind, placebo-controlled trial. Am J Gastroenterol. 113:105–114. DOI: 10.1038/ajg.2017.230. PMID: 29091082. PMCID: PMC5770595.

45. Chang L, Sultan S, Lembo A, Verne GN, Smalley W, Heidelbaugh JJ. 2022; AGA clinical practice guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology. 163:118–136. DOI: 10.1053/j.gastro.2022.04.016. PMID: 35738724.

46. Ishibashi M, Hashimoto F, Kouchi Y, Imaizumi K, Ito F, Yasuda S. 2024; Evaluation and treatment of constipation in pregnancy: Examination using the Japanese version of the constipation evaluation scale. Fukushima J Med Sci. 70:35–47. DOI: 10.5387/fms.2023-25. PMID: 38267029. PMCID: PMC10867430.

47. Yasuda G, Shibata K, Takizawa T, et al. 2002; Prevalence of constipation in continuous ambulatory peritoneal dialysis patients and comparison with hemodialysis patients. Am J Kidney Dis. 39:1292–1299. DOI: 10.1053/ajkd.2002.33407. PMID: 12046044.

48. Sumida K, Yamagata K, Kovesdy CP. 2019; Constipation in CKD. Kidney Int Rep. 5:121–134. DOI: 10.1016/j.ekir.2019.11.002. PMID: 32043026. PMCID: PMC7000799.