Review of Treatment Options for Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation

Figures & data

Figure 1 Disorders of gut–brain interaction exist on a continuum.

Note: © 2016 Rome Foundation, Inc. All Rights Reserved. Modified from Rome Foundation’s Rome IV Functional Gastrointestinal Disorders, Disorders of the Gut-Brain Interaction – Volume II – Page 970.⁵⁶

Abbreviations: CIC, chronic idiopathic constipation; FDr, functional diarrhea; IBS-C, irritable bowel syndrome with constipation; IBS-D, irritable bowel syndrome with diarrhea; IBS-M, irritable bowel syndrome with mixed bowel habits.

Figure 2 Diagnosing IBS-C and CIC.

Note: ^aCriteria fulfilled for the last 3 months with symptom onset at least 6 months before diagnosis.

Abbreviations: BM, bowel movement; BSFS, Bristol Stool Form Scale; CIC, chronic idiopathic constipation; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; IBS-C, irritable bowel syndrome with constipation; SBM, spontaneous bowel movement.

Table 1 Medications Commonly Associated with Constipation

Adrenergic drugs

Analgesics

● NSAIDs

● Opiates

● Tramadol

Anticholinergics

Anticonvulsants

Antihypertensives

● Antiarrhythmic agents

● Calcium channel blockers

● Diuretics

● Furosemide

● Hydrochlorothiazide

Antiparkinsonian drugs

● Dopaminergic agents

Antipsychotics

● Phenothiazine derivatives

Bile salt chelators/bile acid binders

Bisphosphonates

Drugs containing cations

● Aluminum- or calcium-containing antacids

● Bismuth

● Calcium supplements

● Iron supplements

● Lithium

● Sucralfate

Spasmolytics

Tricyclic antidepressants

Abbreviation: NSAID, nonsteroidal anti-inflammatory drug.

Table 2 Overview of Medications Commonly Used in the Management of IBS-C or CIC

	MoA	Indication	Dose and Administration	Efficacy and Safety	Other Considerations	ACG Recommendation^Citation26,Citation27a
OTC medications
Peppermint oil	Smooth muscle relaxant	IBS-C	1–2 capsules TID orally, 15–30 min before food for 1 month^Citation37	Improves abdominal pain, discomfort, and bloating^Citation38 Impact on motility is more limited^Citation38 Most common AE is heartburn	Formulations using novel coating have been developed in an attempt to overcome AEs^Citation38	Weak recommendation for overall symptom improvement in IBS based on low-quality evidence
Polyethylene glycol	Osmotic laxative	IBS-C CIC	17 g/day, dissolved in 8 oz of water^Citation23,Citation39	Improves stool consistency and frequency in IBS-C^Citation26,Citation38 No evidence of improvement in abdominal pain or global symptoms compared with PBO^Citation26,Citation32,Citation38 Common AEs include abdominal pain and headache^Citation11	Not approved for chronic use	Weak recommendation for overall symptom improvement in IBS based on low-quality evidence Strongly recommended for improving CIC symptoms based on high-quality evidence
FDA-approved medications
Linaclotide	GC-C agonist	IBS-C CIC	IBS-C: 290 µg QD CIC: 72 or 145 µg QD To be taken on an empty stomach at least 30 minutes prior to the first meal of the day^Citation40	In IBS-C, significantly more pts receiving linaclotide met the primary efficacy endpoints: ≥30% improvement in WAP and an increase of ≥1 CSBM from baseline within the same wk (≥6/12 wks of treatment FDA endpoint); or ≥3 CSBMs/wk with an increase of ≥1 CSBM from baseline (and component responses) for ≥9/12 wks vs PBO^Citation41,Citation42 In CIC, significantly more pts receiving either dose of linaclotide achieved the primary endpoint compared with PBO (≥3 CSBMs/wk and increase of ≥1 CSBM from baseline for ≥9/12 wks)^Citation43 The most common AEs (reported in ≥2% of pts with IBS-C or CIC) are diarrhea, abdominal pain, flatulence, and abdominal distension^Citation40	Contraindicated in pts <6 years of age and pts with known or suspected mechanical GI obstruction Recommended to avoid linaclotide in pts 6 to <18 years of age^Citation40	Strongly recommended for overall symptom improvement in IBS-C based on high-quality evidence Strongly recommended for treatment of CIC based on high-quality evidence
Lubiprostone	Chloride channel activator	IBS-C (females), CIC	IBS-C: 8 µg BID CIC: 24 µg BID To be taken with food and water^Citation44	Significantly more pts receiving lubiprostone were considered overall responders (reported moderate relief 4 wks/month or significant relief ≥2 wks/month [with no reports of moderate or severely worse relief] for ≥2/3 months) compared with PBO in pts with IBS-C^Citation45 Studies in pts with CIC demonstrated higher frequency of SBMs across 4 wks of treatment in lubiprostone-treated pts compared with PBO-treated pts^Citation44 The most common AEs (reported in >4% of pts): nausea, diarrhea and abdominal pain for IBS-C pts and nausea, headache, abdominal pain, abdominal distension and flatulence for CIC pts^Citation44	Contraindicated in pts with known or suspected mechanical GI obstruction Approved for use in female adult pts with IBS-C; not determined if men with IBS-C respond differently^Citation44	Strongly recommended for overall symptom improvement in IBS-C pts based on moderate-quality evidence Strongly recommended for treatment of CIC based on high-quality evidence
Plecanatide	GC-C agonist	IBS-C CIC	3 mg QD To be taken with or without food^Citation46	In IBS-C, a significantly greater proportion of pts receiving plecanatide were overall responders compared with pts receiving PBO (≥30% improvement in WAP and increase in ≥1 CSBM/wk from baseline for ≥6/12 wks)^Citation47 A significantly greater percentage of durable overall CSBM responders was observed with plecanatide vs PBO in pts with CIC (≥3 CSBMs/wk with an increase of ≥1 CSBM/wk from baseline for ≥9/12 wks including ≥3 of the last 4 wks)^Citation48,Citation49 Diarrhea is the most common AE (occurring in ≥2% of pts)^Citation46^–^Citation49	Contraindicated in pts <6 years of age and pts with known or suspected mechanical GI obstruction Recommended to avoid plecanatide in pts 6 to <18 years of age^Citation46	Recommended for overall symptom improvement in IBS-C based on moderate-quality evidence^b
Prucalopride	5-HT4 receptor agonist	CIC	2 mg QD 1 mg QD for pts with severe renal impairment^Citation50	A significantly greater proportion of pts receiving prucalopride were responders vs pts receiving PBO (responder defined as ≥3 CSBMs/wk over 12 wks)^Citation51,Citation52 The most common AEs (occurring in ≥2% of pts): headache, abdominal pain, nausea, diarrhea, abdominal distension, dizziness, vomiting, flatulence, and fatigue^Citation50	Contraindicated in pts with hypersensitivity to prucalopride or in pts with intestinal perforation or obstruction Pts should be monitored for suicidal ideation and behavior as suicides, suicide attempts, and suicidal ideation have been reported^Citation50	Strongly recommended and determined to be more effective than PBO in improving symptoms of CIC based on moderate-quality evidence^c
Tegaserod	5-HT4 receptor agonist	IBS-C, female pts aged <65 years^d	6 mg BID ≥30 min before meals^Citation53	Significantly greater proportions of pts receiving tegaserod were responders vs pts receiving PBO (responders defined as pts reporting considerable or complete relief of IBS symptoms 2/4 wks or somewhat relieved 4/4 wks)^Citation53 Headache, abdominal pain, nausea, flatulence, dyspepsia, and dizziness are the most common AEs (occurring in ≥2% of pts)	Contraindicated in pts with a history of MI, stroke, intestinal ischemia, severe renal impairment, moderate or severe hepatic impairment, bowel obstruction, symptomatic gallbladder disease, suspected SOD, abdominal adhesions, or hypersensitivity to tegaserod^Citation53 Pts should be monitored for clinical worsening of depression and emergence of suicidal thoughts and behaviors^Citation53	–
Tenapanor^e	NHE3 inhibitor	IBS-C	50 mg, BID To be taken immediately prior to the first and last meals of the day^Citation54	A significantly greater proportion of pts receiving tenapanor were primary responders (defined as simultaneous ≥30% improvement in WAP and increase of ≥1 CSBM/wk from baseline for 6/12 wks)^Citation54 The most common AEs (occurring in ≥2% of pts) are diarrhea, abdominal distension, flatulence, and dizziness^Citation54	Tenapanor is contraindicated in pts <6 years of age and pts with known or suspected mechanical GI obstruction Recommended to avoid tenapanor in pts 6 to <12 years of age^Citation54	–
Non-FDA-approved prescription medications
Antispasmodics	Smooth muscle relaxant	Not approved for use in IBS or CIC	Hyoscyamine, up to 15 mg/day Dicyclomine 20–40 mg QD^Citation37	Can provide short-term symptom relief Effective as a category in IBS, although evidence supporting individual agents is limited^Citation26 Blurred vision, dizziness, and dry mouth are common AEs	–	Weak recommendation for certain antispasmodics (otilonium, pinaverium, hyoscine, cimetropium, drotaverine, and dicyclomine) for overall symptom improvement in IBS based on low-quality evidence
SSRIs: fluoxetine, paroxetine, citalopram	Serotonin reuptake inhibitor	Not approved for use in IBS or CIC	Fluoxetine: 20 mg QD Paroxetine: 10–50 mg QD Citalopram: 20–40 mg QD^Citation37	Effective in providing global symptom relief and improving pain^Citation26,Citation55 Nausea, insomnia, diarrhea or constipation, decreased libido, ejaculatory dysfunction, and weight gain are common AEs^Citation37 Use may be limited by AEs and healthcare provider acceptance^Citation27	Cost of SSRIs may be a concern for some pts^Citation27	Weak recommendation for overall symptom improvement in IBS based on low-quality evidence

Notes: ^aIBS-C recommendations based on the 2018 monograph and CIC recommendations based on the 2014 monograph; ^bplecanatide was approved for treatment of CIC subsequent to the publication of the 2014 monograph for CIC; ^cprucalopride was not available in the US at the time of the 2014 ACG monograph for CIC, but was available in Canada and the European Union; ^dtegaserod was withdrawn from the US market in 2007 owing to concerns about cardiovascular AEs and was approved for this specific patient population in March 2019, subsequent to publication of the monograph; ^etenapanor was approved for treatment of IBS-C in September 2019.

Abbreviations: 5-HT₄, serotonin-4; ACG, American College of Gastroenterology; AE, adverse event; BID, twice daily; CIC, chronic idiopathic constipation; CSBM, complete spontaneous bowel movement; FDA, US Food and Drug Administration; GC-C, guanylate cyclase-C; GI, gastrointestinal; IBS, irritable bowel syndrome; IBS-C, irritable bowel syndrome with constipation; MI, myocardial infarction; mo, month; MoA, mechanism of action; NHE3, sodium/hydrogen exchanger 3; OTC, over-the-counter; PBO, placebo; pts, patients; QD, once daily; SBM, spontaneous bowel movement; SOD, sphincter of Oddi dysfunction; SSRI, selective serotonin reuptake inhibitor; TID, three times daily; WAP, worst abdominal pain; wk, week.

Drossman DA. Rome IV Functional Gastrointestinal Disorders, Disorders of the Gut-Brain Interaction - Volume II. 4th ed. In: Chang L, Chey WD, Kellow J, Tack J, William E. Whitehead WE, Rome IV Committees, Eds. The Rome Foundation; 2016.

 Google Scholar

Ford AC, Moayyedi P, Chey WD, et al. American College of Gastroenterology monograph on management of irritable bowel syndrome. Am J Gastroenterol. 2018;113(Suppl 2):1–18. doi:10.1038/s41395-018-0084-x

 PubMed Web of Science ®Google Scholar

Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol. 2014;109(Suppl 1):S2–S26. doi:10.1038/ajg.2014.187

 PubMed Web of Science ®Google Scholar

Lucak S, Chang L, Halpert A, Harris LA. Current and emergent pharmacologic treatments for irritable bowel syndrome with diarrhea: evidence-based treatment in practice. Therap Adv Gastroenterol. 2017;10(2):253–275. doi:10.1177/1756283X16663396

 PubMed Web of Science ®Google Scholar

Chey WD. Symposium report: an evidence-based approach to IBS and CIC: applying new advances to daily practice: a review of an adjunct clinical symposium of the American College of Gastroenterology Meeting October 16, 2016, Las Vegas, Nevada. Gastroenterol Hepatol (N.Y.) 2017;13(2 suppl 1):1–16.

 PubMedGoogle Scholar

Patel S, DeSimone E, Doerfler BM, Halpert A, Lucak S. Irritable bowel syndrome: practical considerations for nurse practitioners and physician assistants. 2018. Available from: https://www.consultant360.com/article/gastroenterology/irritable-bowel-syndrome/irritable-bowel-syndrome-practical-considerations. Accessed January 21, 2019.

 Google Scholar

DiPalma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol. 2007;102(7):1436–1441. doi:10.1111/j.1572-0241.2007.01199.x

 PubMed Web of Science ®Google Scholar

Chapman RW, Stanghellini V, Geraint M, Halphen M. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. Am J Gastroenterol. 2013;108(9):1508–1515. doi:10.1038/ajg.2013.197

 PubMed Web of Science ®Google Scholar

Saito YA, Schoenfeld P, Locke GR. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002;97(8):1910–1915. doi:10.1111/j.1572-0241.2002.05913.x

 PubMed Web of Science ®Google Scholar

US Food and Drug Administration. Linzess – highlights of prescribing information. 2020. Available from: https://media.allergan.com/actavis/actavis/media/allergan-pdf-documents/product-prescribing/Final_labeling_text_10-2018-AR-updates-LINZESS-clean.pdf. Accessed February, 2021.

 Google Scholar

Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol. 2012;107(11):1714–1724. doi:10.1038/ajg.2012.255

 PubMed Web of Science ®Google Scholar

Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol. 2012;107(11):1702–1712. doi:10.1038/ajg.2012.254

 PubMed Web of Science ®Google Scholar

Lembo AJ, Schneier HA, Shiff SJ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med. 2011;365(6):527–536. doi:10.1056/NEJMoa1010863

 PubMed Web of Science ®Google Scholar

US Food and Drug Administration. Amitiza – highlights of prescribing information. 2020. Available from: https://general.takedapharm.com/amitizapi. Accessed February 26, 2021.

 Google Scholar

Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome – results of two randomized, placebo-controlled studies. Aliment Pharmacol Ther. 2009;29(3):329–341. doi:10.1111/j.1365-2036.2008.03881.x

 PubMed Web of Science ®Google Scholar

US Food and Drug Administration. Trulance – highlights of prescribing information. 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208745s001lbl.pdf. Accessed August, 2020.

 Google Scholar

Brenner DM, Fogel R, Dorn SD, et al. Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. Am J Gastroenterol. 2018;113(5):735–745. doi:10.1038/s41395-018-0026-7

 PubMed Web of Science ®Google Scholar

DeMicco M, Barrow L, Hickey B, Shailubhai K, Griffin P. Randomized clinical trial: efficacy and safety of plecanatide in the treatment of chronic idiopathic constipation. Therap Adv Gastroenterol. 2017;10(11):837–851. doi:10.1177/1756283X17734697

 PubMed Web of Science ®Google Scholar

Miner PB Jr, Koltun WD, Wiener GJ, et al. A randomized Phase III clinical trial of plecanatide, a uroguanylin analog, in patients with chronic idiopathic constipation. Am J Gastroenterol. 2017;112(4):613–621. doi:10.1038/ajg.2016.611

 PubMed Web of Science ®Google Scholar

US Food and Drug Administration. Prucalopride – highlights of prescribing information. 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210166s000lbl.pdf. Accessed July 26, 2019.

 Google Scholar

Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med. 2008;358(22):2344–2354. doi:10.1056/NEJMoa0800670

 PubMed Web of Science ®Google Scholar

Quigley EMM, Vandeplassche L, Kerstens R, Ausma J. Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation – a 12-week, randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2009;29(3):315–328. doi:10.1111/j.1365-2036.2008.03884.x

 PubMed Web of Science ®Google Scholar

US Food and Drug Administration. Zelnorm – highlights of prescribing information. 2019. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021200Orig1s015lbl.pdf. Accessed April 22, 2019.

 Google Scholar

US Food and Drug Administration. IBSRELA – highlights of prescribing information. 2019. Available from: https://ardelyx.com/wp-content/uploads/2019/09/PI-Approval.pdf. Accessed December 13, 2019.

 Google Scholar

Ford AC, Talley NJ, Schoenfeld PS, Quigley EMM, Moayyedi P. Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009;58(3):367–378. doi:10.1136/gut.2008.163162

 PubMed Web of Science ®Google Scholar