A Therapeutic Review of Chronic Constipation
Release Date: December 1, 2015
Expiration Date: December 31, 2017
Alyssa Teehan, PharmD Candidate
Jade Peoples, PharmD Candidate
Jeffrey A. Kyle, PharmD, BCPS
Associate Professor of Pharmacy Practice
Rebekah Bradford, PharmD Candidate
Samford University McWhorter School of Pharmacy
FACULTY DISCLOSURE STATEMENTS:
Dr. Kyle and Mss. Teehan, Peoples, and Bradford have no actual or potential conflicts of interest in relation to this activity.
Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge
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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.
To update participants on the pharmacotherapeutic management of chronic constipation, including dosage and administration for existing agents and safety and efficacy data on current and experimental therapies.
After completing this activity, the participant should be able to:
- Define chronic constipation according to Rome III criteria and identify risk factors associated with the disorder.
- Identify the advantages and disadvantages of the various treatment options for chronic constipation.
- Develop an appropriate pharmacotherapeutic and monitoring plan for a patient with chronic constipation.
- Describe the pharmacist's role in the management of chronic constipation.
ABSTRACT: Chronic constipation is broadly defined as the occurrence of fewer than three bowel movements per week for at least 3 months in a 6-month period. Annually, this disorder accounts for a significant number of office visits, as well as hospitalizations. Chronic constipation may be due to opioid use, an ileus secondary to surgery, or unknown reasons. While there are many OTC therapies, other treatments are available only by prescription, and some are restricted to registered hospitals. Additionally, a number of potential new therapies are currently being researched. Pharmacists can play a key role in assisting patients who are experiencing chronic constipation, and for that reason they should be well-informed about the various treatment options.
Chronic constipation is a common functional gastrointestinal (GI) disorder that affects between 2% and 27% of the general population in the United States, depending on the definition of constipation used and the population studied.1,2 About 70% to 90% of persons who experience constipation suffer from chronic constipation.3 In the U.S. alone, chronic constipation results in more than 2.5 million physician visits and more than 100,000 hospital visits per year.1,3 According to two studies, between 1995 and 2003 the annual average medical cost for chronic constipation in the United States was estimated to be $250 to $500 per patient.4,5 Out-of-pocket expenses per patient per year were estimated to be $400.4
A number of definitions for constipation are found in the literature. Most commonly, constipation is characterized by difficult or incomplete defecation resulting in fewer than three bowel movements per week in the absence of alarm symptoms.6 Alarm symptoms (TABLE 1) are worsening symptoms that may be a sign of systemic pathology (e.g., malignancy) and require a referral to a physician or specialist, such as a gastroenterologist. For constipation to be considered chronic, the patient must be symptomatic for at least 3 months.1,6,7 Patients often describe constipation as straining, passing hard or infrequent stools, or abdominal discomfort or pain. The Rome III criteria are a combination of standard indicators for diagnosing various GI disorders, including chronic constipation.1 Constipation is most prevalent in the elderly population, especially females.6 Other populations prone to chronic constipation include children, pregnant females, patients of lower socioeconomic status, postoperative patients, and persons taking pain medications.2,6
Three common types of chronic constipation are opioid-induced constipation (OIC), postoperative ileus (POI), and chronic idiopathic constipation (CIC). The incidence of OIC has been rising because of the significant increase in prescribed opioids.8,9 Opioids decrease peristalsis and the secretion of fluid in the GI tract by binding to mu, kappa, and delta receptors.8,9 Most patients do not develop tolerance to OIC, thereby rendering aggressive treatment necessary. POI is a common complication of surgery that most often occurs after intra-abdominal surgery because of local trauma to the gut during the procedure.10 The resulting absence of peristalsis leads to nausea, vomiting, abdominal pain, distention, and ultimately constipation.10 Patients whose constipation has no discernible mucosal or structural cause are diagnosed with CIC, also known as functional constipation.11,12 CIC is diagnosed based on the fre quency of bowel symptoms, and it shares many GI symptoms with constipation-predominant irritable bowel syndrome (IBS-C).11,12
Therapeutic options for the various types of chronic constipation have increased over the years. Pharmacists are in a key position to help patients who have chronic constipation; therefore, they should be knowledgeable about the various treatment options. This article will provide an overview of chronic constipation and its various therapies.
PATHOPHYSIOLOGY AND ETIOLOGY
Dyssynergia of the abdominal, rectal, and pelvic-floor muscles, rectal hyposensitivity, a paradoxical increase in sphincter pressure, less than 20% relaxation of anal sphincter pressure, and inadequate abdominal-rectal propulsive forces interrupt the normal defecation cycle and cause constipation.1,13 The causes of constipation are diverse and multifaceted; however, constipation can generally be classified into two main categories: primary and secondary. Primary constipation is usually due to functional or anatomical abnormalities, which include normal-transit, slow-transit, and defecation disorders.13 Secondary constipation stems from medications, obstruction, or metabolic, neurologic, systemic, or psychiatric causes (TABLE 2). For constipation to be classified as primary, all secondary causes must be ruled out first.
CIC, sometimes also called fiber-deficient constipation, is the most common type of primary constipation; it is characterized by normal stool frequency with hard stools and painful defecation.13 Slow-transit constipation is primarily found in young women and is characterized by infrequent stools caused by delayed colonic transit time.1,13 Defecation disorders are due to ano-rectal dysfunction or dyssynergia caused by the failure to permit stool release.1 Patients usually present with a variety of symptoms, including less-frequent bowel movements, painful or difficult bowel movements, straining, hard or dry stool, bloating, abdominal discomfort or pain, incomplete emptying, nausea, fatigue, and loss of appetite.14
The Rome Foundation is an independent not-for-profit organization that provides clinicians with a standard set of criteria to assist in the diagnosis of a variety of functional GI disorders. The most recent diagnostic criteria (Rome III), published in 2006, state that a patient must experience two or more of the following symptoms for at least 25% of defecations in order to be diagnosed with chronic constipation: straining; hard or lumpy stools; incomplete excretion; blockage; maneuvers to aid excretion; rarely, loose stool without the use of laxatives; or fewer than three defecations per week.6,13 Furthermore, constipation must be present for at least 3 months within a 6-month period.6,13 Other causes, including IBS, must be ruled out before these criteria are applied.6,13
The primary management of chronic constipation begins with diet and lifestyle modifications. Diet is an important factor in reversing the effects of constipation. Patients should eat foods rich in fiber and low in fat, such as fruit, vegetables, legumes, and whole grains.6,14 The recommended daily amount of fiber is approximately 25 g.6 A fiber supplement may be necessary if the patient is unable to consume an adequate amount of dietary fiber. Patients, particularly those supplementing with fiber, should increase their water intake to approximately 2 L daily and decrease their consumption of caffeinated, alcoholic, and sugary beverages.6,14,15 In addition to making dietary modifications, patients should exercise at least 30 minutes daily.6,14,16 Avoidance of stress and the practice of relaxation techniques are also viable methods if the cause of constipation is stress-related.
Should a patient fail to respond to lifestyle modifications, secondary causes, such as medications, should be explored. If a medication is identified as the potential culprit, the dosage should be reduced or the medication discontinued entirely.6,14 In the event that diet and lifestyle modifications fail to elicit a response and secondary causes have been ruled out, pharmacotherapy may be required. The medication classes prescribed to treat constipation include laxatives, chloride channel activators, peripherally acting mu-opioid receptor antagonists (PAMORAs), and guanylate cyclase C (GC-C) receptor agonists (TABLE 3).6,14 There are also a number of new medications in development. The American College of Gastroenterology (ACG) has recently provided guidance on the various therapeutic options for chronic constipation.17
Bulk-Forming Agents: These agents, which are considered first-line treatment for chronic constipation, include soluble (e.g., psyllium) and insoluble fibers (e.g., calcium polycarbophil, methylcellulose, bran). These agents use water to enlarge and soften the stool, thereby increasing the frequency of bowel movements.18 For bulk-forming agents to work, the patient must drink plenty of water; otherwise, worsening constipation and bloating may occur.18 Based on the literature, psyllium appears to have the best evidence for use compared with other bulk-forming agents. Adverse effects (AEs) such as delayed gastric emptying, loss of appetite, bloating, gas, and distention may limit the use of these agents, especially insoluble fibers.1,19
Osmotic Laxatives: If bulk-forming agents are not effective or tolerated, osmotic laxatives (e.g., polyethylene glycol [PEG], lactulose, sorbitol, magnesium) may be tried.17 These work by drawing water into the colon to soften the stool and enhance its passage.13,18 PEG and lactulose have the best evidence and the strongest ACG recommendations for use in chronic constipation.15 Some studies indicate that low-dose PEG is more effective than lactulose.19 PEG doses should be slowly titrated up since PEG has been shown to cause an excessive frequency of stools, especially in the elderly.1 The effectiveness of sorbitol, a sugar alcohol, is comparable to that of lactulose, as shown in a randomized, double-blind, crossover trial.18,19 The use of magnesium-based products is not supported by any placebo-controlled trials, and these products should be used with caution in elderly patients, especially those with acute or chronic kidney disease.18,19 Patients may experience nausea, flatulence, bloating, cramping, and diarrhea when using osmotics.1,19
Stimulant Laxatives: Bisacodyl and senna are recommended in patients with a suboptimal response to osmotic laxatives.17 Stimulant laxatives work by stimulating peristaltic contractions through the myenteric plexus and inhibiting water absorption.18 Because of a lack of long-term trial data and concerns about rebound constipation when stopped abruptly, stimulant laxatives should not be used for long-term treatment.1,17 Large doses of stimulant laxatives should be avoided, as they may cause liquid stool and increase abdominal cramping.19
Stool Softeners: Softeners such as docusate sodium work by exercising a detergent effect on stool that increases the amount of fluid passing into the stool.19 There is little evidence to support the routine recommendation of docusate sodium, as this agent has been shown to be inferior to psyllium.20 Mineral oil, an emollient, is used to lubricate and emulsify the stool to ease bowel movements (BMs).19 Evidence supporting the use of mineral oil is poor, and this agent is associated with malabsorption of fat-soluble vitamins, seepage, incontinence, and (seldom) aspiration pneumonia.18,19 Based on these AEs and scant evidence, mineral oil is not preferred for constipation.
Chloride Channel Activators
Lubiprostone is a prostaglandin E analogue that selectively activates type 2 chloride channels, promoting the secretion of intestinal fluid into the intestinal lumen and thereby softening stools.21,22 In several studies, lubiprostone increased spontaneous BMs (SBMs), shortened the time to first SBM within 24 hours of initiation, alleviated constipation-related symptoms (e.g., bloating, straining, stool viscosity), and reduced the need for additional laxatives.23-27 Therefore, lubiprostone is FDA-approved for the treatment of CIC, IBS-C in women older than 18 years, and OIC in chronic non-cancer pain.23 Lubiprostone has very little systemic bioavailability and acts locally in the GI tract, which limits its potential for drug interactions.22
According to clinical trials, lubiprostone is generally well tolerated. The most common AEs reported with lubiprostone use are nausea, diarrhea, and headache.23,28 The administration of lubiprostone with food can reduce nausea.23 Lubiprostone has the potential to cause dyspnea within 1 hour of the first dose, but this generally resolves within 3 hours.23 Lubiprostone is contraindicated in patients with mechanical GI obstruction, and dosage adjustments should be made in patients with severe hepatic impairment.23 While it strongly supports the use of lubiprostone as an option for chronic constipation, the ACG does not state whether it should be considered primary therapy or reserved for patients who have failed previous therapies (e.g., laxatives).17
PAMORAs can effectively treat constipation without affecting analgesia.9 There are three agents in this class: alvimopan, methylnaltrexone, and naloxegol.
Alvimopan: This selective PAMORA was FDA-approved in 2008 for chronic constipation in patients recovering from partial large-bowel or small-bowel resection with primary anastomosis.9,29 The indication was limited to a specific population because the majority of clinical trials for alvimopan were conducted in patients undergoing abdominal surgery. Overall, data indicate that alvimopan significantly accelerates the time to GI-motility recovery, with the first BM occurring about 48 hours post surgery; it also improves the time to toleration of solid food.9,29,30 The approved dosage for POI is 12 mg administered at least 30 minutes prior to surgery, followed by 12 mg orally twice daily for up to 7 days.9, 29,30 In studies, the AE profile of alvimopan was similar to that of placebo, with GI complaints (e.g., constipation, flatulence, dyspepsia) being the most common AE.9,29
In addition to GI complaints, an increase in myocardial infarction was noted in a 12-month study evaluating the use of alvimopan for OIC. As a result, the FDA requires a Risk Evaluation and Mitigation Strategy program known as Entereg Access Support and Education (E.A.S.E.). This program limits the distribution of alvimopan to registered hospitals that have met predetermined requirements (TABLE 4). In general, alvimopan is not recommended for patients with severe hepatic impairment and it is contraindicated in patients who have received therapeutic doses of opioids for more than 7 days before the time alvimopan would be initiated.29,30 Based on mixed results, alvimopan is not presently FDA-approved for OIC.31,32
Methylnaltrexone Bromide: This is the first PAMORA approved for OIC in patients receiving palliative care who have previously failed laxative therapy.33,34 Data on the use of methylnaltrexone for those outside a palliative-care environment are limited. Because methylnaltrexone bromide is a quaternary amine, it has poor lipid solubility, allowing the drug to antagonize mu-opioid receptors peripherally in the GI tract without reversing analgesic effects.33,34 Although methylnaltrexone can be administered SC, IV, and orally, the FDA-approved route is SC injection. Nevertheless, the various formulations of methylnaltrexone have resulted in similar outcomes of significantly reversing OIC and decreasing oral-cecal transit times.9,34 One study tested methylnaltrexone 0.15 mg/kg SC every other day for 2 weeks versus placebo in palliative-care patients who had received opioids and laxatives for at least 2 weeks without symptom improvement.9 The study found methylnaltrexone to be superior to placebo, with the first BM occurring 4 hours post administration.9
The recommended daily dose is determined by obtaining the patient’s weight and rounding to the appropriate vial size.9 Based on a phase III trial, the oral formulation of methylnaltrexone relieves OIC with doses ranging from 300 mg to 450 mg compared with placebo.33 In this trial, the first BM occurred within 4 hours at higher doses and was maintained another 8 weeks post administration.33 Initially, methylnaltrexone should be administered every other day and, if needed, can be given daily. The dosage, however, should be reduced in patients with renal impairment (creatinine clearance <30 mL/min). Common AEs associated with methylnaltrexone include abdominal pain, flatulence, nausea, dizziness, and diarrhea.34 Additionally, severe AEs, such as GI perforation, have occurred in patients with decreased structural integrity of the GI-tract wall.34 Methylnaltrexone is contraindicated in patients with mechanical GI obstruction.34
Naloxegol: This PAMORA is a new oral, pegylated derivative of naloxone. Naloxegol blocks mu-opioid receptors peripherally without reversing analgesic effects. The safety and efficacy of naloxegol have been established in several trials. Two multicenter, double-blind, placebo-controlled, phase III trials examined naloxegol 12.5 mg and 25 mg versus placebo.35 The primary end point of these trials was a response of more than three BMs in 1 week and at least a one-BM increase from baseline.35 Secondary end points included time to first BM, average number of BMs, severity of straining, hardness of stool, and the need for rescue laxative use.35 In both trials, the end points were achieved with nal-oxegol 25 mg; the 12.5-mg dose demonstrated mixed results.35 Therefore, the recommended dose of naloxegol is 25 mg orally once daily at least 1 hour before a meal on an empty stomach.35 Naloxegol is contraindicated with the use of strong CYP3A4 inducers and inhibitors.35 With moderate CYP3A4 inhibitors, a dose adjustment of 12.5 mg is required.27 The main AEs associated with naloxegol are abdominal pain, diarrhea, nausea, and vomiting.27
GC-C agonists act as secretagogues to treat chronic constipation locally in the intestines.21,36 Linaclotide is a 14-amino-acid GC-C agonist that binds and activates GC-C, triggering an increase in cyclic guanosine monophosphate.21 This increase stimulates the secretion of chlorine and bicarbonate via activation of the cystic fibrosis transmembrane conductance regulator, resulting in an increase in luminal-fluid secretion and a reduction in colonic transit time.21,36 The approval of linaclotide was based on two 12-week randomized, double-blind, placebo-controlled clinical trials of lina-clotide 145 mg and 290 mg versus placebo once daily.22,37 Outcome data demonstrated that linaclotide increased the percentage of patients who reached the primary end point of three or more BMs per week, compared with placebo.22,37 The effects of linaclotide were observed within the first 24 hours and continued through 16 weeks.37 The most common AE was diarrhea.1 Clinical trials have demonstrated that linaclotide improves stool consistency, straining, abdominal discomfort, bloating, global assessments, and quality of life.1 As with lubiprostone, the ACG strongly supports the use of linaclotide for the treatment of chronic constipation but gives no guidance on linaclotide’s place in the treatment algorithm.
Probiotics are live organisms that deliver a health benefit when consumed, owing to their viability in the gastric lumen and their ability to adhere to the intestinal epithelium.38,39 Generally, for a therapeutic effect, a dose of at least 1 billion colony-forming units should be taken daily.38 Two organisms that are able to treat constipation are Bifidobacterium and Lactobacillus. Two randomized studies showed that probiotics containing Bifidobacterium lactis DN-173 010 increase evacuation frequency significantly compared with placebo.38 Additionally, B lactis HN019 can shorten the intestinal transit time in a dose-dependent manner.38 One study found that Lactobacillus casei Shirota improved constipation symptoms compared with placebo.38,39 Another study investigated whether the combination of a pre-biotic containing polydextrose Lactobacillus acidophilus and a probiotic containing B lactis HN019 had an effect on intestinal transit in patients with constipation and found that the combination, administered in yogurt, considerably shortened the colonic transit time after 2 weeks.38 While probiotics appear to be another viable option for patients experiencing chronic constipation, the ACG has not fully embraced this treatment.17
RESEARCH INTO NEW CHRONIC CONSTIPATION THERAPIES
Naldemedine and axelopran are two PAMORAs currently being investigated for use in noncancer patients with OIC.6 Naldemedine is a once-daily medication that has undergone a phase III trial showing improved frequency of SBM compared with placebo over 12 weeks.40,41 Naldemedine appears to be well tolerated, with GI complaints reported most commonly.41 Axelopran (TD-1211) has completed phase II testing for noncancer patients with OIC.8 Early outcomes indicate that axelopran administered orally once daily increases BMs and shortens time to the first BM.8 The most common AEs with axelopran were abdominal pain, nausea, vomiting, and headache.8
5-HT4 Receptor Agonists
Serotonin (5-HT) plays an important role in gastric motility and secretions through 5-HT3 and 5-HT4 receptors.42 When activated, 5-HT4 receptors in the gut cause an increase in colonic motility, secretions, and peristaltic contractions.42 Since the removal of cisapride and tegaserod from the market because of cardiovascular effects, several drugs have been developed to target the 5-HT4 receptor. Prucalopride, currently approved for use only in Europe and Asia, is a highly selective 5-HT4 agonist that has been shown to improve BMs and other symptoms related to constipation, with no cardiovascular AEs.42-45 Other agents under development in this class include renzapride (5-HT4 agonist and 5-HT3 and 5-HT2b antagonist), velusetrag (5-HT4 agonist), and naronapride (5-HT4 agonist).46,47 The most common AEs to date are headache, diarrhea, nausea, and abdominal pain.47
Plecanatide is a new investigational 16-amino-acid GC-C agonist. Plecanatide works by mimicking the effects of uroguanylin, which activates the GC-C receptor.22,36 Activation of the GC-C receptor leads to the secretion of fluid into the intestinal lumen, thereby facilitating BMs. Plecanatide is currently undergoing phase III clinical trials. Preliminary results indicate that plecanatide is well tolerated and improves stool frequency and consistency, straining, and quality of life.22
Ileal Bile Acid Transporter Inhibitor
Another new target for treating constipation is inhibiting ileal bile acid transporter (IBAT) reabsorption. The IBAT inhibitor elobixibat (A3309) inhibits the reuptake of bile acids, ultimately leading to an acceleration of colonic transit time.12 One randomized, clinical trial found that elobixibat 10 mg taken for 14 days decreased colonic transit time, reduced total cholesterol and LDL, and increased C4 levels.12 Another randomized, controlled clinical trial demonstrated that elobixibat accelerated colonic transit at 24 hours and 48 hours versus placebo.12,42 In this trial, AEs associated with elobixibat were dose-dependent and included abdominal pain or discomfort and diarrhea.12,42 Another clinical trial found that elobixibat 10 mg and 15 mg increased BMs, but that the 5-mg dosage was ineffective.12 Overall, the 10-mg dosage had the best efficacy-to-safety ratio for treating CIC.12 In current completed trials, lower-abdominal cramping and diarrhea were commonly reported AEs.12
If constipation is not treated properly, serious complications can ensue. Hemorrhoids, probably the best-known complication of constipation, result from sustained straining and elevated intra-abdominal pressure.18 Fecal incontinence is the result of new stool bypassing old, hardened stool that is blocking the colon. Anal fissure is a tear in the lining of the anus that usually occurs during excretion of hard stool. In women, chronic constipation can cause organ prolapse, in which pelvic organs such as the bladder, rectum, uterus, and vagina can slip out of place. Fecal impaction that results in colonic obstruction can occur in patients with chronic constipation, and treatment usually requires surgery. Chronic constipation may even lead to serious complications such as bowel perforation, which can lead to stool seepage into the body cavity and—although rare—death.18
THE PHARMACIST’S ROLE
Patients regularly seek out pharmacists for assistance with a variety of ailments, particularly GI complaints such as constipation. Therefore, it is the responsibility of the pharmacist to advise patients about the risks and benefits of therapy, maintain the competence of the various treatments as well as preventive strategies, and be prepared to answer common questions surrounding expectations and outcomes.
A considerable number of chronic constipation therapies are available OTC. The pharmacist, however, should not recommend medications without first counseling patients on appropriate diet and lifestyle modifications for alleviating constipation. Patients should be instructed to eat a diet rich in fiber and low in fat, as well as to maintain adequate hydration and exercise regularly. The pharmacist should obtain an accurate medication history to determine that no medications are responsible for the constipation. If a medication is identified as a potential cause, the patient should be encouraged to discuss the problem with the prescriber so that alterations to the regimen can be made. If secondary causes have been ruled out and therapy is warranted, the pharmacist should help the patient select appropriate agents and provide education about the product’s safety and efficacy.
Although laxatives remain first-line therapy for chronic constipation, the pharmacist should be aware of the potential for misuse and abuse of these drugs. Laxatives may be sought by individuals seeking to lose weight for sports competitions or by those with eating disorders, such as anorexia.48 If either scenario is suspected, the pharmacist should not make recommendations but should refer the patient to a physician instead.
Other reasons pharmacists may refer patients to a physician rather than providing therapeutic recommendations include complicated comorbidities, constipation lasting longer than 1 week, symptoms of severe vomiting, rectal bleeding, and pregnancy. Pharmacists also play a key role in ensuring the proper use of prescription medications. Regardless of practice setting, pharmacists should be familiar with the E.A.S.E. program for alvimopan. Finally, pharmacists should remain up-to-date on potential therapies that may soon be available and, therefore, impact current therapeutic recommendations.
In summary, pharmacists can play a key role in assisting patients who are experiencing chronic constipation. Given their accessibility, pharmacists should be prepared to answer key questions related to this challenging disorder and, at a minimum, understand the various therapies available.
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- Suares NC, Ford AC. Prevalence of, and risk factors for, chronic idiopathic constipation in the community: systematic review and meta-analysis. Am J Gastroenterol. 2011;106:1582-1591.
- Dik VK, Siersema PD, Joseph A, et al. Constipation-related direct medical costs in 16 887 patients newly diagnosed with chronic constipation. Eur J Gastroenterol Hepatol. 2014;26:1260-1266.
- Nyrop KA, Palsson OS, Levy RL, et al. Costs of health care for irritable bowel syndrome, chronic constipation, functional diarrhoea and functional abdominal pain. Aliment Pharmacol Ther. 2007;26:237-248.
- Singh G, Lingala V, Wang H, et al. Use of health care resources and cost of care for adults with constipation. Clin Gastroenterol Hepatol. 2007;5:1053-1058.
- Lindberg G, Hamid SS, Malfertheiner P, et al. World Gastroenterology Organisation global guideline: constipation—a global perspective. J Clin Gastroenterol. 2011;45:483-487.
- Brandt LJ, Prather C, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(suppl 1):S5-S21.
- Leppert W. Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction. Drug Des Devel Ther. 2015;9:2215-2231.
- Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106:835-843.
- Lee TH, Lee JS, Hong SJ, et al. Risk factors for postoperative ileus following orthopedic surgery: the role of chronic constipation. J Neurogastroenterol Motil. 2015;21:121-125.
- Heidelbaugh JJ, Stelwagon M, Miller SA, et al. The spectrum of constipation-predominant irritable bowel syndrome and chronic idiopathic constipation: US survey assessing symptoms, care seeking, and disease burden. Am J Gastroenterol. 2015;110:580-587.
- Mosinska P, Fichna J, Storr M. Inhibition of ileal bile acid transporter: an emerging therapeutic strategy for chronic idiopathic constipation. World J Gastroenterol. 2015;21:7436-7442.
- Andrews CN, Storr M. The pathophysiology of chronic constipation. Can J Gastroenterol. 2011;25(suppl B):16B-21B.
- Hunt R, Quigley E, Abbas Z, et al. Coping with common gastrointestinal symptoms in the community: a global perspective on heartburn, constipation, bloating, and abdominal pain/discomfort May 2013. J Clin Gastroenterol. 2014;48:567-578.
- Manz F. Hydration and disease. J Am Coll Nutr. 2007;26(suppl5):S535-S541.
- Costilla VC, Foxx-Orenstein AE. Constipation: understanding mechanisms and management. Clin Geriatr Med. 2014;30:107-115.
- Ford AC, Moayyedi P, Lacey 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.
- Leung L, Riutta T, Kotecha J, Rosser W. Chronic constipation: an evidence-based review. J Am Board Fam Med. 2011;24:436-451.
- Portalatin M, Winstead N. Medical management of constipation. Clin Colon Rectal Surg. 2012;25:12-19.
- McRorie JW, Daggy BP, Morel JG, et al. Psyllium is superior to docusate sodium for treatment of chronic constipation. Aliment Pharmacol Ther. 1998;12:491-497.
- Thayalasekeran S, Ali H, Tsai HH. Novel therapies for constipation. World J Gastroenterol. 2013;19:8247-8251.
- Thomas RH, Luthin DR. Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents. Pharmacotherapy. 2015;35:613-630.
- Amitiza (lubiprostone) product information. Bethesda, MD: Sucampo Pharma Americas, LLC, and Deerfield, IL: Takeda Pharmaceuticals America, Inc; April 2013.
- Jamal MM, Adams AB, Jansen JP, Webster LR. A randomized, placebo-controlled trial of lubiprostone for opioid-induced constipation in chronic noncancer pain. Am J Gastroenterol. 2015;110:725-732.
- Johanson JF, Morton D, Geenen J, Ueno R. Multicenter, 4-week, double-blind, randomized, placebo-controlled trial of lubiprostone, a locally-acting type-2 chloride channel activator, in patients with chronic constipation. Am J Gastroenterol. 2008;103:170-177.
- Johanson JF, Ueno R. Lubiprostone, a locally acting chloride channel activator, in adult patients with chronic constipation: a double-blind, placebo-controlled, dose-ranging study to evaluate efficacy and safety. Aliment Pharmacol Ther. 2007;25:1351-1361.
- Barish CF, Drossman D, Johanson JF, Ueno R. Efficacy and safety of lubiprostone in patients with chronic constipation. Dig Dis Sci. 2010;55:1090-1097.
- Fukudo S, Hongo M, Kaneko H, Ueno R. Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized, placebo-controlled and dose-finding study. Neurogastroenterol Motil. 2011;23:544-e205.
- Erowele GI. Alvimopan (Entereg), a peripherally acting mu-opioid receptor antagonist for postoperative ileus. P T. 2008;33:574,580-583.
- Entereg (alvimopan) product information. Whitehouse Station, NJ: Merck & Co, Inc; August 2015.
- Irving G, Pénzes J, Ramjattan B, et al. A randomized, placebo-controlled phase 3 trial (Study SB-767905/013) of alvimopan for opioid-induced bowel dysfunction in patients with non-cancer pain. J Pain. 2011;12:175-184.
- Moss J, Rosow CE. Development of peripheral opioid antagonists: new insights into opioid effects. Mayo Clin Proc. 2008;83:1116-1130.
- Wang CZ, Yuan CS. Pharmacologic treatment of opioid-induced constipation. Expert Opin Investig Drugs. 2013;22:1225-1227.
- Kumar L, Barker C, Emmanuel A. Opioid-induced constipation: pathophysiology, clinical consequences, and management. Gastroenterol Res Pract. 2014;2014:141737.
- Bruner HC, Atayee RS, Edmonds KP, Buckholz GT. Clinical utility of naloxegol in the treatment of opioid-induced constipation. J Pain Res. 2015:8;289-294.
- Gonzalez-Martinez MA, Ortiz-Olvera NX, Mendez-Navarro J. Novel pharmacological therapies for management of chronic constipation. J Clin Gastroenterol. 2014;48:21-28.
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