Many patients with chronic constipation, including irritable bowel syndrome with constipation (IBS-C), begin treatment with over-the-counter options such as polyethylene glycol 3350 (MiraLAX) and soluble fiber such as psyllium (Metamucil). These are evidence-based therapies, but they may not provide adequate relief for patients with more severe, persistent, or treatment-resistant symptoms. Current guidelines support escalation to prescription treatment when appropriately selected over-the-counter therapy has not worked well enough.^1,2

We prescribe several targeted therapies that work through different mechanisms. Treatment is selected according to the type of constipation, predominant symptoms, prior response, other medical conditions, potential adverse effects, dosing preferences, and medication access.^1,2

Motegrity (prucalopride)

Prucalopride is a selective serotonin 5-HT₄ receptor agonist and gastrointestinal prokinetic. It stimulates colonic peristalsis, including high-amplitude propagating contractions that help move stool through the colon. It is FDA approved for chronic idiopathic constipation (CIC) in adults. The usual adult dose is 2 mg once daily, with a lower dose recommended for severe renal impairment, and it may be taken with or without food.^1,3

Prucalopride is more receptor-selective than older prokinetic drugs such as cisapride. Available clinical-trial and observational data support a favorable cardiovascular safety profile, without the same cardiac safety signal associated with older, less selective agents. This does not mean that treatment is risk-free, so the patient’s medical history and other medications still need to be reviewed.^3,4

Across six pivotal trials, the primary responder endpoint was assessed over 12 weeks. Approximately 19% to 38% of patients receiving prucalopride achieved an average of at least three complete spontaneous bowel movements per week, compared with approximately 10% to 20% of patients receiving placebo. Improvements in bowel-movement frequency were observed as early as the first week. These results show clinically meaningful benefit for a significant subset of patients.³

Secretagogues

Secretagogues act locally in the intestine to increase electrolyte and fluid secretion. Linaclotide and plecanatide activate guanylate cyclase-C pathways that increase chloride- and bicarbonate-rich fluid secretion, whereas lubiprostone activates intestinal chloride-channel pathways. The resulting increase in luminal fluid softens stool and can accelerate intestinal transit. Their mechanisms differ from that of osmotic laxatives such as polyethylene glycol, which primarily retain water in the bowel through an osmotic effect.^5,6,7

• Linaclotide (Linzess): Linaclotide is a guanylate cyclase-C agonist approved for CIC and IBS-C. In adults, the labeled dose is 290 mcg once daily for IBS-C and 145 mcg once daily for CIC, although a 72-mcg dose may be used for CIC according to the patient’s presentation or tolerability. It should be taken on an empty stomach at least 30 minutes before a meal. Linaclotide can improve bowel symptoms and abdominal symptoms in IBS-C. Diarrhea is its most important common adverse effect.^2,5
• Plecanatide (Trulance): Plecanatide is another guanylate cyclase-C agonist approved for CIC and IBS-C in adults. The recommended dose is 3 mg once daily. Unlike linaclotide, plecanatide may be taken with or without food. Individual response and tolerability vary, so one guanylate cyclase-C agonist may work better for a particular patient even though no agent is universally superior for everyone.^2,6
• Lubiprostone (Amitiza): Lubiprostone activates intestinal chloride channels to increase fluid secretion. The labeled adult dose is 24 mcg twice daily for CIC. For IBS-C, the labeled dose is 8 mcg twice daily, and the current US indication is limited to women 18 years of age and older. Lubiprostone should be taken with food and water. Nausea is a common adverse effect and may be reduced by taking the medication as directed with food and water.^1,2,7

These medications can improve bowel frequency, stool consistency, straining, and, depending on the diagnosis and medication, abdominal symptoms. They do not work for every patient, and adverse effects such as diarrhea, nausea, or abdominal discomfort may determine which treatment is most appropriate.^1,2,5,6,7

Opioid-induced constipation: PAMORAs

For patients whose constipation is caused or worsened by opioid pain medication, we may prescribe a peripherally acting μ-opioid receptor antagonist (PAMORA). These medications block opioid receptors in the gastrointestinal tract while being designed to limit penetration into the central nervous system. They therefore generally treat opioid-related slowing of the bowel without requiring a change in the underlying analgesic regimen.^8,9,10,11

PAMORAs should not be described simply as gut-selective naloxone or Narcan. Although central opioid effects are usually preserved, opioid-withdrawal symptoms or reduced analgesia can occur, particularly in patients with impaired blood-brain barrier integrity. These agents are also contraindicated in patients with known or suspected gastrointestinal obstruction, and their prescribing information includes warnings about gastrointestinal perforation in susceptible patients.^9,10,11

• Methylnaltrexone (Relistor): Methylnaltrexone is available as oral tablets and a subcutaneous injection. For opioid-induced constipation associated with chronic noncancer pain, labeled adult dosing is 450 mg orally each morning or 12 mg subcutaneously once daily. For advanced illness, the injection is dosed according to body weight and is generally administered every other day as needed. Renal or hepatic impairment may require dose adjustment.⁹
• Naloxegol (Movantik): Naloxegol is an oral PAMORA used for opioid-induced constipation in adults with chronic noncancer pain. The usual labeled dose is 25 mg once daily, taken on an empty stomach at least 1 hour before the first meal of the day or 2 hours after the meal. A lower dose may be appropriate for certain patients with renal impairment, adverse effects, or interacting medications.¹⁰
• Naldemedine (Symproic): Naldemedine is taken orally at a dose of 0.2 mg once daily and may be taken with or without food. It is approved for opioid-induced constipation in adults with chronic noncancer pain.¹¹

Guidelines recommend conventional laxatives as initial therapy for opioid-induced constipation. For patients whose symptoms remain inadequately controlled despite laxatives, the American Gastroenterological Association recommends naldemedine or naloxegol and suggests methylnaltrexone. In appropriately selected patients, these medications can provide meaningful improvement without routinely compromising pain control.⁸

Tenapanor (Ibsrela)

Tenapanor is an oral medication with a mechanism distinct from secretagogues and prokinetic drugs. It locally inhibits the sodium/hydrogen exchanger 3 (NHE3) on the intestinal surface. This reduces intestinal sodium absorption, increases water within the intestinal lumen, accelerates transit, and produces softer stool.¹²

Tenapanor is FDA approved for IBS-C in adults. The recommended dose is 50 mg twice daily, taken immediately before breakfast or the first meal of the day and immediately before dinner. Clinical trials support improvement in IBS-C bowel and abdominal symptoms. Reduced visceral hypersensitivity has also been demonstrated in animal models, although that preclinical finding should not be presented as a fully established human mechanism.^2,12

Tenapanor provides an additional option for patients whose IBS-C has not responded adequately to other treatments or whose symptom profile, tolerability, and dosing preferences make an NHE3 inhibitor appropriate. Diarrhea is its most common adverse effect and can occasionally be severe.^2,12

Our approach

We match treatment to the likely cause of constipation, the patient’s predominant symptoms, prior treatment response, and relevant safety considerations:

• Chronic idiopathic constipation: We begin with appropriate dietary measures and over-the-counter therapy when suitable. If those measures are inadequate, guideline-supported prescription options include linaclotide, plecanatide, prucalopride, and lubiprostone. Prucalopride is one of several evidence-based next-line treatments.¹
• IBS-C with significant abdominal pain: Linaclotide has the strongest recommendation in the current American Gastroenterological Association IBS-C pharmacologic guideline. Plecanatide, tenapanor, and lubiprostone are additional guideline-supported options, with selection based on symptoms, adverse-effect risk, previous response, dosing considerations, and access.²
• Opioid-induced constipation: Conventional laxatives are generally used first. A PAMORA may be appropriate when constipation remains inadequately controlled, provided that obstruction and other important contraindications have been excluded.^8,9,10,11
• Treatment-resistant constipation: We confirm that appropriate medications have been tried at adequate doses and durations. Sequential trials or carefully supervised combination therapy may be appropriate. Before labeling constipation as refractory, patients should be evaluated for secondary causes and for defecatory disorders. Anorectal manometry, balloon-expulsion testing, and pelvic-floor biofeedback may be needed when pelvic-floor dysfunction is suspected.^13,14

We also review fiber intake and tolerance, overall diet, fluid intake, physical activity, and medications that may worsen constipation. We investigate secondary causes when the history or examination suggests them. Testing for conditions such as hypothyroidism should be targeted to the clinical presentation rather than ordered automatically for every patient with constipation.^13,14

Our goal is to achieve regular, comfortable bowel movements and meaningful improvement in the symptoms that matter to the patient. When fiber, polyethylene glycol, and other basic measures are clearly inadequate, the answer is not simply to repeat “drink more water” indefinitely. A more useful approach is to identify the constipation subtype and select a therapy that addresses the relevant physiology while monitoring efficacy, adverse effects, and quality of life.^1,2,13,14

This information is educational and does not replace an individualized medical evaluation. Medication selection, dosing, contraindications, interactions, and monitoring should be reviewed with a qualified prescribing clinician.

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References

1. Chang L, Chey WD, Imdad A, et al. American Gastroenterological Association-American College of Gastroenterology clinical practice guideline: pharmacological management of chronic idiopathic constipation. Am J Gastroenterol. 2023;118(6):936-954. doi:10.14309/ajg.0000000000002227.
2. Chang L, Sultan S, Lembo A, Verne GN, Smalley W, Heidelbaugh JJ. AGA clinical practice guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology. 2022;163(1):118-136. doi:10.1053/j.gastro.2022.04.016.
3. National Library of Medicine. Motegrity (prucalopride) tablets, for oral use: prescribing information. DailyMed. Updated July 17, 2025. Accessed June 20, 2026. View prescribing information.
4. Tack J, Derakhchan K, Gabriel A, et al. A review of the cardiovascular safety of prucalopride in patients with chronic idiopathic constipation. Am J Gastroenterol. 2023;118(6):955-960. doi:10.14309/ajg.0000000000002249.
5. National Library of Medicine. Linzess (linaclotide) capsules, for oral use: prescribing information. DailyMed. Updated May 21, 2026. Accessed June 20, 2026. View prescribing information.
6. National Library of Medicine. Trulance (plecanatide) tablets, for oral use: prescribing information. DailyMed. Updated April 4, 2024. Accessed June 20, 2026. View prescribing information.
7. National Library of Medicine. Amitiza (lubiprostone) capsules, for oral use: prescribing information. DailyMed. Updated September 11, 2025. Accessed June 20, 2026. View prescribing information.
8. Crockett SD, Greer KB, Heidelbaugh JJ, Falck-Ytter Y, Hanson BJ, Sultan S; American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association Institute guideline on the medical management of opioid-induced constipation. Gastroenterology. 2019;156(1):218-226. doi:10.1053/j.gastro.2018.07.016.
9. National Library of Medicine. Relistor (methylnaltrexone bromide) tablets and injection: prescribing information. DailyMed. Updated May 1, 2024. Accessed June 20, 2026. View prescribing information.
10. National Library of Medicine. Movantik (naloxegol) tablets, for oral use: prescribing information. DailyMed. Updated November 27, 2024. Accessed June 20, 2026. View prescribing information.
11. National Library of Medicine. Symproic (naldemedine) tablets, for oral use: prescribing information. DailyMed. Updated July 25, 2025. Accessed June 20, 2026. View prescribing information.
12. National Library of Medicine. Ibsrela (tenapanor) tablets, for oral use: prescribing information. DailyMed. Updated May 28, 2025. Accessed June 20, 2026. View prescribing information.
13. Staller K, Neshatian L, Lembo A, Bharucha AE. AGA clinical practice update on evaluation and management of refractory constipation: expert review. Clin Gastroenterol Hepatol. 2026;24(2):296-305. doi:10.1016/j.cgh.2025.09.031.
14. Bharucha AE, Lacy BE. Mechanisms, evaluation, and management of chronic constipation. Gastroenterology. 2020;158(5):1232-1249.e3. doi:10.1053/j.gastro.2019.12.034.