In most countries, constipation is prevalent in both children

case-based review Evaluation and Management of Chronic Constipation in Clinical Practice Case Study and Commentary, Arnold Wald, MD cme jointly sponsored by Wayne State University School of Medicine and JCOM This article has a companion CME exam that follows the article. To earn credit, read the article and complete the CME evaluation on pages 419 and 420. Estimated time to complete this activity is 1 hour. Faculty disclosure information appears on page 417. Program Audience Primary care physicians. Educational Needs Addressed Constipation is a prevalent condition that disproportionately affects women and older adults. It accounted for approximately 38,000 hospital visits and 5.7 million office visits, mostly to primary care physicians, in 2001. Many patients with constipation are able to self-treat with over-the-counter laxatives and fiber supplements; however, in some cases, constipation may become debilitating and unresponsive to these interventions, resulting in medical consultation. It also has been shown to impair health-related quality of life. As primary care physicians play a key role in managing patients with constipation, it is important that they be familiar with diagnostic and therapeutic strategies for this disorder. Educational Objectives After participating in this CME activity, primary care physicians should be able to 1. Describe the diagnostic tests recommended for the evaluation of chronic constipation 2. Discuss effective therapies for chronic constipation 3. State the tests used in the workup of patients who do not respond to conservative therapy 4. Identify which patients with chronic constipation should be referred to a gastroenterologist for further evaluation In most countries, constipation is prevalent in both children and adults and is a complaint often seen in clinical practice. Estimates of the prevalence of constipation in the general population vary according to how constipation is defined. The previous, narrow definition of constipation as bowel infrequency has been broadened to encompass difficult defecation (Table 1) [1,2], a concept that is highly subjective and hard to quantify. With definitions of constipation that include difficulties with defecation and selfperceived constipation, prevalence rates increase to as high as 27% [3], with considerable variability among countries. In all populations, constipation is more common in women, children, and the elderly [3]. As with many functional disorders, constipation is often mild and intermittent. The availability of over-the-counter (OTC) laxatives and fiber supplements has led to much self-treatment; in the United States, more than $800 million is spent on laxatives each year [4]. Constipation can become debilitating and unresponsive to simple interventions, resulting in medical consultation. In 2001, constipation accounted for approximately 38,000 hospital visits and 5.7 million office visits, mostly to primary care physicians [5]. There are no data regarding the additional costs of constipation that are generated as a result of medical evaluations, diagnostic studies, and surgery. CASE STUDY Initial Presentation A 26-year-old secretary presents to her primary care physician complaining of chronic constipation of several years duration. History The patient reports having difficulty with defecation for the past 3 years. On average, she has 4 bowel movements per week, which are often small and passed with considerable straining. She often feels a sense of incomplete emptying of her bowels and is bloated after meals with lower abdominal distention. She denies heartburn, early satiety, abdominal From the Section of Gastroenterology and Hepatology, University of Wisconsin School of Medicine and Public Health, Madison, WI. www.turner-white.com Vol. 14, No. 7 July 2007 JCOM 411

chronic constipation Table 1. American College of Gastroenterology Task Force: Definitions of Chronic Constipation Unsatisfactory defecation characterized by infrequent stool, difficult stool passage, or both Difficult stool passage includes: Straining Hard/lumpy stool Difficulty passing stool Incomplete evacuation Prolonged evacuation Prolonged time to stool Need for manual maneuvers to pass stool Symptoms must be reported for at least 3 months Adapted with permission from Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol 2005;100 Suppl 1: S5 S21. Copyright 2005, with permission from Elsevier. cramps, excessive flatulence, weight loss, or episodes of diarrhea. Her menses are regular and she denies urinary symptoms. The patient is married with 1 child, age 5, who is well. There is no family history of gastrointestinal disorders. She is otherwise well, exercises at a gym 4 times a week, does not smoke, and eats a healthy diet with ample portions of vegetables and fruits, fiber cereals, and at least 8 glasses of water daily. She has used proprietary laxatives at times with variable success. Physical Examination The patient appears healthy with a blood pressure of 120/ 60 mm Hg, heart rate of 62 bpm and regular, height of 63", and weight of 115 lb (body mass index, 22.8 kg/m 2 ). Her thyroid is not enlarged, heart and lungs are normal, and abdomen is soft and nontender with no masses or organomegaly. Rectal examination reveals normal anal sphincter tone and strength and no perianal deformities, prolapse, or hemorrhoids. Stool is firm and hemoccult-negative. What causes constipation? Risk factors associated with constipation include low income, low educational levels, physical inactivity, depression, increasing age, and low caloric intake [3]. Contrary to general belief, low levels of dietary fiber and decreased fluid intake have not been associated with constipation in large population studies [6]. Constipation can be conceptually regarded as disordered movement of stool through the colon or anorectum [7]. It can Table 2. Secondary Causes of Functional Constipation* Metabolic and endocrine disorders Diabetes mellitus Hypothyroidism Hypercalcemia, hypokalemia Pregnancy Porphyria Panhypopituitarism Neurogenic disorders Hirschsprung s disease Chagas disease Neurofibromatosis Permission electronically reproduce this table Ganglioneuromatosis not granted by copyright holder. Autonomic neuropathy Intestinal pseudo-obstruction (myopathy, neuropathy) Multiple sclerosis Spinal cord lesions Parkinson s disease Collagen vascular and muscle disorders Systemic sclerosis Amyloidosis Dermatomyositis Myotonic dystrophy Adapted by permission of Blackwell Science, Inc, from Wald A. Chronic constipation: advances in management. Neurogastroenterol Motil 2007;19:4 10. *Partial list. occur as a result of a primary motor disorder, in association with numerous diseases, or as a side effect of many drugs (Table 2 and Table 3). Chronic illnesses often lead to physical and mental impairments that can produce or exaggerate constipation. Lack of physical mobility can render a person unable to respond to defecatory signals because of inadequate toileting arrangements. Other contributory factors to constipation in the bedridden patient include medications and dietary inadequacies. Generalized weakness or neuromuscular diseases can result in poor expulsion efforts. Nevertheless, most patients with chronic constipation have no obvious cause of their symptoms and are designated as having an idiopathic disorder. What diagnostic tests are recommended for the evaluation of chronic constipation? In the general population, constipation is usually mild and intermittent and often responds to self-medication with readily available OTC medications. When a patient presents with 412 JCOM July 2007 Vol. 14, No. 7 www.turner-white.com

case-based review constipation, an extensive workup should not be performed unless alarm symptoms (eg, anemia, weight loss, blood in stools, abdominal mass, nausea/vomiting, anorexia, a recent change in bowel movement) are present or if clinical judgment deems it necessary [2]. The initial approach to such patients generally entails empirically treating constipation with little or no workup. Initial Assessment This patient s constipation is chronic and stable and she does not have any alarm symptoms. A complete blood count is normal. The physician feels further workup (eg, serum calcium, thyroid function testing, routine electrolytes) is not necessary and that there is no indication for flexible sigmoidoscopy, colonoscopy, or barium enema. A decision is made to treat the patient empirically. How efficacious are the therapies for chronic constipation? Are the new drugs for constipation cost-effective? The first choice of many patients for constipation is fiber supplements (bulking agents), which are readily available in some foods or as OTC preparations. Although a deficiency of dietary fiber uncommonly causes constipation, some individuals do respond to an increase in fiber intake of 20 to 30 g daily [8]. Fiber has been shown to increase stool weight and decrease transit time through the gastrointestinal tract [9]. Although soluble fibers such as psyllium and calcium polycarbophil may be better tolerated than insoluble fibers [10], this varies greatly among patients. Patients should be told that improvement is often not immediate and the amount of fiber should be increased slowly over 1 to 2 weeks. Fiber should be used cautiously in patients with irritable bowel syndrome, as they often experience increased bloating and cramping. It is best to discuss these potential side effects with patients who have irritable bowel syndrome before starting treatment in order to increase the chances of compliance. As a general rule, fiber intake should be minimized in patients with megacolon, megarectum, colonic inertia, and defecation disorders [11]. If fiber supplements are ineffective or poorly tolerated, osmotic laxatives may be tried (Table 4). These agents work by retaining fluid in the lumen by osmotic forces; efficacy is well established for most osmotic laxatives [2,12,13]. Magnesium-containing agents are usually the initial choice because they are inexpensive and readily available without a prescription. However, they should be used with caution in patients with renal insufficiency. Nonabsorbable sugars (eg, lactulose, sorbitol) are degraded by colonic bacteria into low-molecular-weight acids that function to osmotically Table 3. Various Drugs Associated with Constipation Anticholinergics Antispasmodics Antidepressants Antipsychotics Cation-containing agents Iron supplements Aluminum Permission (antacids, to electronically sucralfate) reproduce this table Neurally active agents not granted by copyright holder. Opiates Antihypertensives Ganglionic blockers Vinca alkaloids Calcium channel blockers 5HT 3 antagonists Adapted by permission of Blackwell Science, Inc, from Wald A. Chronic constipation: advances in management. Neurogastroenterol Motil 2007;19:4 10. retain fluid in the lumen. These may produce increased gas and bloating as a byproduct, which are generally less prominent with polyethylene glycol (PEG), which is not degraded by intracolonic bacteria. PEG-containing solutions have been shown to be effective in both short- and long-term studies [12,14]. Osmotic laxatives should be used daily and titrated to best effect. However, they may be ineffective and counterproductive in patients with colonic inertia, megacolon, and defecation disorders [11]. Stimulant laxatives such as senna (anthraquinones) and bisacodyl (diphenylmethanes) are time-honored agents that work by increasing fluid accumulation and stimulating colonic motor activity. They have been unfairly criticized as causing cancer, producing laxative addiction and dependency, and harming the colon if used for long periods of time. These allegations have not been substantiated [6,13]. Stimulant laxatives are cost-effective and produce satisfactory results in many patients. They may be given alone or in addition to bulking or osmotic agents. The U.S. Food and Drug Administration (FDA) has approved 2 agents for chronic constipation in the last few years. The first agent is tegaserod, a partial serotonin 5-hydroxytryptamine 4 (HT 4 ) agonist, which acts to facilitate gastrointestinal motility [15,16]. Sales and marketing of this drug were recently suspended at the request of the FDA because of an increased risk of cardiovascular events compared with that of placebo. More recently approved is lubiprostone, which works by stimulating specific intestinal chloride channels (CIC-2) and therefore increasing intestinal fluid secretion [17]. Both drugs have been shown to be effective, with a therapeutic gain over placebo of 5% to 15% in www.turner-white.com Vol. 14, No. 7 July 2007 JCOM 413

chronic constipation Table 4. Representative Agents for Treatment of Constipation Laxative Usual Adult Dose Onset of Action Cost (30 days)* Bulk-forming laxatives Psyllium 1 tsp 1 3 times daily 12 72 hr $7.34 $22.02 Methylcellulose 1 tsp 1 3 times daily 12 72 hr $2.80 $7.50 Wheat dextrin 3 9 tablets daily 24 48 hr $10.80 $32.40 Osmolar agents Polyethylene glycol 8.5 34 g in 240 ml liquids 2 4 days $20.85 $83.38 Lactulose 20 g daily 24 48 hr $40.02 Sorbitol 21 g daily 24 48 hr $11.00 Magnesium hydroxide 2.4 g daily 0.5 3 hr $13.61 Stimulant laxatives Bisacodyl 10 mg daily 6 10 hr $7.78 Senna 2 tablets daily 6 12 hr $1.68 Other agents Lubiprostone 24 μg twice daily 24 hr $187.90 *Prices obtained at www.drugstore.com. Accessed May 2007. most studies. Lubiprostone, however, is costly and should not be used as a first-line agent (Table 4). No trial or meta-analysis has yet demonstrated that one laxative is more effective than another or that lubiprostone or tegaserod are better than less expensive agents. A reasonable approach is to start with an osmotic and/or stimulant laxative if the response to fiber supplements is unsatisfactory. If this regimen does not relieve constipation, use of lubiprostone should be considered or the patient should be referred to a gastroenterologist for further evaluation. Initial Management The primary care physician has not identified an obvious cause of constipation in this young woman. There is no evidence of an eating disorder, use of medications that can cause or aggravate constipation, or underlying illnesses known to be associated with constipation. She consumes sufficient dietary fiber and fluids and complains of bloating. A decision is made to begin PEG and to use bisacodyl or senna if she feels that evacuation is incomplete. A prescription is given for PEG 17 g powder in 8 oz of fluid every morning with instructions to increase the dose by 8.5 g every 5 days to a maximum of 34 g daily if constipation does not improve. She also is instructed to use bisacodyl 10 mg at bedtime if she does not experience a complete and satisfactory bowel movement after 3 days. The patient is also told to call the office in 2 weeks to report her clinical progress. After 2 weeks, there is little if any change in bowel habits, bisacodyl causes cramps, and the patient is more bloated. Senna has also been ineffective. Lubiprostone 24 µg twice daily is prescribed. Although the patient has no side effects except for very mild nausea, her bowel habits remain unsatisfactory. The patient is told to stop the drug and is referred to a gastroenterologist. What are the reasons that a constipated patient does not respond satisfactorily to conservative therapy? What tests are of value in the medical workup of such patients? The most problematic patients with chronic constipation are those who fail to respond to medical therapy and in whom an explanation should be sought. It is intuitive that idiopathic constipation in many patients is associated with disordered movement of stool through the colon or anorectum. Colonic transit studies using radiopaque markers have identified subgroups of constipated patients who have slow transit through the colon and/or the rectosigmoid colon. Slow colonic transit is a heterogenous disorder, which may be associated with neuroenteric changes in the colon [18] or related to disorders such as anorexia nervosa or to medications associated with slowing of intestinal transit. However, many patients are found to have normal colonic transit when tested. This suggests other diagnostic possibilities, such as the presence of a defecation disorder alone, an intermittent colonic dysfunction not present during testing, a misperception of normal bowel functions, or simply an insensitivity of a single test to detect colonic dysmotility. A relatively recent major advance with important therapeutic ramifications is the characterization of a number of defecation disorders, such as dyssynergic defecation and its 414 JCOM July 2007 Vol. 14, No. 7 www.turner-white.com

case-based review functional equivalent, inadequate expulsion [19]. Because symptoms do not always predict whether such a disorder is present, the diagnosis currently depends upon physiologic testing, which is best done in laboratories with experience with specific diagnostic testing [20,21]. In general, the use of colonoscopy and imaging studies has been excessive in patients with constipation and should be minimized [2,22]. Colonic Transit Studies It is often argued that colonic transit studies, which measure the movement of radiopaque markers through the colon over 5 to 7 days, are unnecessary in patients with refractory constipation because treatment will be similar regardless of findings. This point of view is debatable for several reasons. The demonstration of slow colonic transit while consuming a 20- to 25-g fiber diet suggests that fiber supplementation and osmotic laxatives are likely to be ineffective and even counterproductive by causing increased bloating and discomfort. Such patients often experience some relief on less fiber and osmotic laxatives and, instead, on prokinetic agents or stimulant laxatives. Conversely, the demonstration of normal colonic transit suggests a possible defecation disorder and should reassure the physician and patient that colonic motor function is intact. Although patterns of slow colonic transit do not always predict pathophysiology, some general conclusions can be made that are of practical clinical value [1,7,20]. The finding of slow transit in the rectum and sigmoid colon with normal transit proximally strongly suggests anorectal dysfunction, such as a defecation disorder or a behavioral problem (eg, withholding). Slow transit in the right colon with normal anorectal testing suggests a neuroenteric disorder in the absence of known conditions that may slow transit. Analyzing patterns of slow colonic transit helps to distinguish subsets of patients and to identify rational treatment options when trying to manage the refractory patient. Anorectal Studies for Defecation Disorders Anorectal manometry provides information on rectal sensation and compliance, relaxation of the internal anal sphincter, and patterns produced on attempted expulsion of the apparatus [23 25]. A rectal balloon provides an indication of the intra-abdominal pressures generated during expulsion efforts, whereas pressure recordings of the anal sphincters indicate relaxation or inappropriate contraction of the external anal sphincter. In patients with dyssynergic defecation, there is an increase in external sphincter pressures during attempted expulsion of the balloon [19]. Patients who exhibit this finding often are unable to expel a 50-mL water-filled balloon within 60 seconds while seated on a commode [20,21], a test that can easily be used as an office-based screening method. Anterior rectoceles are outpouchings of the rectovaginal wall into the lumen of the vagina, which can be palpated with the patient bearing down as if to defecate or can be identified on barium defecography. Barium defecography is used with varying degrees of enthusiasm, but I order it infrequently when searching for possible rectoceles or enteroceles. The test has poor interobserver reproducibility and generally contributes little to therapeutic decision making [25]. The relationship between rectoceles and a preexisting defecation disorder is unknown, that is, whether prolonged straining results in rectocele formation, which in turn results in stool trapping and prolonged straining when the rectocele reaches a critical size. However, it is evident that most rectoceles are asymptomatic, but defecation difficulties may occasionally arise when expulsive forces are misdirected into a large pouch. The key to management is to identify defecation difficulties prior to surgical repair of the rectocele [24]. Choosing a Diagnostic Strategy As mentioned earlier, most chronically constipated patients do not require diagnostic studies beyond taking a careful history and performing a physical examination, including examination of the rectum and pelvic floor. Colonoscopy or flexible sigmoidoscopy is indicated specifically in the presence of alarm symptoms (recent worsening of constipation, blood in the stools, weight loss, anorexia, nausea, vomiting) or as a screening procedure in patients older than 50 years [2]. As symptoms do not discriminate between physiologic subgroups of patients who do not respond to conservative treatment, the workup is similar regardless of presenting symptoms [7]. The most useful diagnostic studies to obtain are a prospective bowel diary recorded over the course of 2 weeks and measurement of colonic transit time. Screening for a defecation disorder can be done using a simple handmade device to measure the expulsion of a balloon filled with 50 ml of water. Normal colonic transit studies and balloon expulsion testing may reassure both the physician and patient that colorectal function is not seriously impaired. If the balloon expulsion test is abnormal, the patient should be referred for anorectal manometry. Upon completion of these studies, 4 patterns of colonic and anorectal function are possible (Figure). Gastroenterology Workup After confirming the history and previous examination, including the patient s failure to respond to conservative therapy, the gastroenterologist arranges for a colonic transit study and balloon expulsion test. During the transit studies, markers move normally through the right and left colon but are delayed through the rectosigmoid www.turner-white.com Vol. 14, No. 7 July 2007 JCOM 415

chronic constipation Colonic transit time and balloon expulsion Both normal Outlet delay and/or no balloon expulsion and abnormal manometry Slow colonic transit; normal expulsion Slow colonic transit, no balloon expulsion, and abnormal anorectal manometry Normal Defecation disorder Slow transit constipation Slow transit and defecation disorder Figure. Patterns of colonic and anorectal function after colonic transit and balloon expulsion studies. region. The patient also is unable to expel a 50-mL waterfilled balloon after 2 minutes of persistent attempts to do so. A defecation disorder is suspected. The patient is then referred for anorectal manometry at a local tertiary center. During attempted expulsion of the catheter, intra-abdominal pressures are appropriately increased, but the patient contracts the external anal sphincter, increasing anal canal pressures inappropriately rather than the normal relaxation and lowering of pressures that are observed in control subjects. A diagnosis of dyssynergic defecation is made [19]. What treatments are available for defecation disorders and what is the evidence to support them? Biofeedback is an effective therapy specifically for constipation caused by dyssynergic defecation [26 29]. Normal defecation involves a coordinated cascade of events: intraabdominal pressures increase while anal canal pressures decrease, and pelvic floor muscles relax to straighten the anorectal angle. In some constipated patients, the anal sphincters do not relax or instead contract to increase anal canal pressures, the puborectalis muscle does not relax or instead contracts to narrow the anorectal angle, and/or inadequate intra-abdominal pressures are generated. Dyssynergic defecation is a relatively new concept and has been given a variety of names, including pelvic floor dysfunction, pelvic floor dyssynergia, and outlet obstruction. Biofeedback therapy is an effective treatment in a high percentage of patients with documented dyssynergic defecation. Successfully treated patients report subjective improvement in symptoms and objective improvement in stool frequency, laxative use, straining, and bloating [26 29]. Candidates should undergo balloon expulsion studies and anorectal manometry to establish the diagnosis [19] before being offered biofeedback therapy, which is time-intensive, requires highly trained and dedicated personnel, and is relatively expensive. Biofeedback works to improve coordination of the pelvic floor, specifically, perception and response to rectal distension as well as the muscular relaxation of the pelvic floor. These functions are controlled partially at a cortical level, which allows them to be altered with conscious efforts. Biofeedback works by providing visual feedback to patients in the form of pressure recordings or electromyographic tracings. Training sessions last approximately 30 to 45 minutes and are provided weekly or several times per week until coordination is established or until treatment is deemed unsuccessful. First, patients are taught to strain more effectively and coordinate expulsion efforts with breathing. Then, they are taught to relax the pelvic floor muscles and sphincter while straining. Finally, patients practice defecating and are given encouragement. With visual feedback and practice, the patient is able to master the physical skills of perceiving rectal distension and relaxing pelvic floor muscles while straining to defecate. As biofeedback often results in good outcomes, including improved quality of life, and it entails no risks, this behavioral therapy should be the first line of therapy in patients found to have dyssynergic defecation. A possible alternative to biofeedback therapy is injection of botulinum toxin A (BTXa) into the puborectalis muscle bilaterally using endoscopic ultrasound guidance [30,31]. A recent open-labeled trial reported a high rate of success with apparent durability and no significant morbidity [31]. 416 JCOM July 2007 Vol. 14, No. 7 www.turner-white.com

case-based review Randomized, controlled, double-blind studies are needed to confirm these findings before BTXa treatments are recommended. Treatment and Outcome The patient is referred to a physical therapist with training and experience with instrumental biofeedback. She receives 5 training sessions, each lasting 30 to 45 minutes, on a weekly basis. In the laboratory, she normalizes defecation patterns first with the use of visual feedback and then with her view of the tracing blocked. The patient s clinical complaints resolve, and 3 months after completion of training, she reports an average of 5 bowel movements weekly without laxatives, less bloating, and no sense of incomplete emptying of the rectum. SUMMARY Constipation is a common complaint in clinical practice and, in the absence of alarm symptoms, may be satisfactorily managed with several available proprietary and prescription drugs without substantial diagnostic testing. A relatively small number of patients will not respond and often benefit from studies that evaluate colonic and anorectal function, including colonic transit studies, anorectal manometry, and balloon expulsion testing. Defecation disorders such as dyssynergia often respond to biofeedback, and BTXa injection into the puborectalis muscle may be an alternative if biofeedback is not available. Evidence to support pharmacologic treatment for the relatively few patients with slow transit constipation is anecdotal and is best managed by gastroenterologists with experience in motility disorders. Corresponding author: Arnold Wald, MD, Section of Gastroenterology & Hepatology, 600 Highland Ave., H6/516 CSC, Madison, WI 53792-5124, axw@medicine.wisc.edu. Financial disclosures: Dr. Wald receives research support from Boehringer Ingelheim; is a consultant for Boehringer Ingelheim, Microbia, Novartis, and Sucampo; and is on the speaker s bureau of Sucampo. References 1. Longstreth GF, Thompson WG, Chey WD, et al. Functional bowel disorders [published erratum appears in Gastroenterology 2006;131:688]. Gastroenterology 2006;130:1480 91. 2. Brandt LJ, Prather CM, Quigley EM, et al. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol 2005;100 Suppl 1:S5 S21. 3. Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic review. Am J Gastroenterol 2004;99:750 9. 4. Faigel DO. A clinical approach to constipation. Clin Cornerstone 2002;4:11 21. 5. Martin BC, Barghout V, Cerulli A. Direct medical costs of constipation in the United States. Manag Care Interface 2006;19: 43 9. 6. Muller-Lissner SA, Kamm MA, Scarpignato C, Wald A. Myths and misconceptions about chronic constipation. Am J Gastroenterol 2005;100:323 42. 7. Wald A. Pathophysiology, diagnosis and current management of chronic constipation. Nat Clin Pract Gastroenterol Hepatol 2006;3:90 100. 8. Voderholzer WA, Schatke W, Muhldorfer BE, et al. Clinical response to dietary fiber treatment of chronic constipation. Am J Gastroenterol 1997;92:95 8. 9. Muller-Lissner SA. Effect of wheat bran on weight of stool and gastrointestinal transit time: a meta-analysis. Br Med J (Clin Res Ed) 1988;296:615 7. 10. Bijkerk CJ, Muris JW, Knottnerus JA, et al. Systematic review: the role of different types of fibre in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2004;19:245 51. 11. Wald A. Chronic constipation: advances in management. Neurogastroenterol Motil 2007;19:4 10. 12. Corazziari E, Badiali D, Bazzocchi G, et al. Long-term efficacy, safety, and tolerability of low daily doses of isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in the treatment of functional chronic constipation. Gut 2000;46: 522 6. 13. Wald A. Constipation in the primary care setting: current concepts and misconceptions. Am J Med 2006;119:736 9. 14. DiPalma JA, DeRidder PH, Orlando RC, et al. A randomized, placebo-controlled, multicenter study of the safety and efficacy of a new polyethylene glycol laxative. Am J Gastroenterol 2000; 95:446 50. 15. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol 2004;2:796 805. 16. Kamm M, Muller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, doubleblind, placebo-controlled, multinational study [published erratum appears in Am J Gastroenterol 2005;100:735]. Am J Gastroenterol 2005;100:362 72. 17. Lacy BE, Campbell Levy L. Lubiprostone: a chloride channel activator. J Clin Gastroenterol 2007;41:345 51. 18. Bassotti G, Villanacci V. Slow transit constipation: a functional disorder becomes an enteric neuropathy. World J Gastroenterol 2006;12:4609 13. 19. Bharucha AE, Wald A, Enck P, Rao S. Functional anorectal disorders. Gastroenterology 2006;130:1510 8. 20. Rao SS, Ozturk R, Laine L. Clinical utility of diagnostic tests for constipation in adults: a systematic review. Am J Gastroenterol 2005;100:1605 15. 21. Minguez M, Herreros B, Sanchiz V, et al. Predictive value of the balloon expulsion test for excluding the diagnosis of pelvic floor dyssynergia in constipation. Gastroenterology 2004;126:57 62. 22. Pepin C, Ladabaum U. The yield of lower endoscopy in patients with constipation: survey of a university hospital, a public county hospital, and a Veterans Administration medical center. Gastrointest Endosc 2002;56:325 32. 23. Sun WM, Rao SS. Manometric assessment of anorectal function. Gastroenterol Clin North Am 2001;30:15 32. www.turner-white.com Vol. 14, No. 7 July 2007 JCOM 417

chronic constipation 24. Cheung O, Wald A. Review article: the management of pelvic floor disorders. Aliment Pharmacol Ther 2004;19:481 95. 25. Diamant NE, Kamm MA, Wald A, Whitehead WE. AGA technical review on anorectal testing techniques. Gastroenterology 1999;116:735 60. 26. Chiarioni G, Salandini L, Whitehead WE. Biofeedback benefits only patients with outlet dysfunction, not patients with isolated slow transit constipation. Gastroenterology 2005;129:86 97. 27. Chiarioni G, Whitehead WE, Pezza V, et al. Biofeedback is superior to laxatives for normal transit constipation due to pelvic floor dyssynergia. Gastroenterology 2006;130:657 64. 28. Rao SS, Seaton K, Miller M, et al. Randomized controlled trial of biofeedback, sham feedback, and standard therapy for dyssynergic defecation. Clin Gastroenterol Hepatol 2007;5:331 8. 29. Heymen S, Scarlett Y, Jones K, et al. Randomized, controlled trial shows biofeedback to be superior to alternative treatments for patients with pelvic floor dyssynergia-type constipation. Dis Colon Rectum 2007;50:428 41. 30. Ron Y, Avni Y, Lukovetski A, et al. Botulinum toxin type-a in therapy of patients with anismus. Dis Colon Rectum 2001;44: 1821 6. 31. Maria G, Cadeddu F, Brandara F, et al. Experience with type A botulinum toxin for treatment of outlet-type constipation. Am J Gastroenterol 2006;101:2570 5. Copyright 2007 by Turner White Communications Inc., Wayne, PA. All rights reserved. 418 JCOM July 2007 Vol. 14, No. 7 www.turner-white.com

JCOM CME CME EVALUATION: Evaluation and Management of Chronic Constipation in Clinical Practice DIRECTIONS: Each of the questions below is followed by 4 possible answers. Select the ONE lettered answer that is BEST in each case and circle the corresponding letter on the answer sheet. 1. A 51-year-old woman with chronic constipation undergoes screening colonoscopy as an average-risk patient. The colonoscopy report reveals dark brown pigment throughout the colon (melanosis coli). Which of the following laxatives causes this condition? A. Bisacodyl B. Lactulose C. Magnesium citrate D. Senna 2. Which of the following drugs used to treat chronic constipation was recently suspended by the U.S. Food and Drug Administration because of possible increased cardiovascular events? A. Lactulose B. Lubiprostone C. Phenolphthalein D. Tegaserod 3. Which of the following has been demonstrated to be highly effective in patients with dyssynergic defecation? A. Biofeedback B. Botulinum toxin injection C. Kegel exercises D. Puborectalis myotomy 4. A 35-year-old healthy woman presents to the primary care physician because of chronic constipation. She has had constipation intermittently since college, but it has become more severe during the last 3 years despite fiber supplements, fluids, and exercise. Which of the following statements regarding additional workup in this case is TRUE? A. She should undergo colonoscopy to the cecum to exclude organic diseases B. She should undergo balloon expulsion and anorectal manometry to evaluate for defecation disorders C. Because of the patient s age and absence of alarm symptoms, an extensive workup is not necessary D. It would be appropriate to obtain serum calcium and thyroid function studies to exclude endocrinologic disorders 5. Which of the following works by stimulating chloride channels in the small intestine? A. Bisacodyl B. Lubiprostone C. Polyethylene glycol D. Tegaserod www.turner-white.com Vol. 14, No. 7 July 2007 JCOM 419

JCOM CME EVALUATION FORM: evaluation and Management of Chronic Constipation in Clinical Practice Participants may earn 1 credit by reading the article named above and correctly answering at least 70% of the accompanying test questions. A certificate of credit and the correct answers will be mailed within 6 weeks of receipt of this page to those who successfully complete the test. Circle your answer to the CME questions below: 1. A B C D 2. A B C D 3. A B C D 4. A B C D 5. A B C D Please answer the following questions: 1. How would you rate this educational activity overall? Excellent Good Fair Poor 2. This article was fair, balanced, free of commercial bias, and fully supported by scientific evidence. Yes No 3. Please rate the clarity of the material presented in the article. Very clear Somewhat clear Not at all clear 4. How helpful to your clinical practice was this article? Very helpful Somewhat helpful Not at all helpful 5. What changes will you make in your practice as a result of reading this article? 6. What topics would you like to see presented in the future? Release date: 15 July 2007 Expiration date: 30 July 2008 Please print clearly: Name: MD/DO/Other: Address: City: State: Zip: Phone: Fax: E-mail: Are you a health care professional licensed to practice in the US/ Canada who can use Category 1 AMA PRA CME credit to fulfill educational requirements? Yes No Physicians are required to report the actual amount of time spent on the activity, up to the maximum designated 1 hour. The actual time spent reading this article and completing the test was. Please mail or fax this sheet to: Wayne State University, Division of CME 101 E. Alexandrine, Lower Level Detroit, MI 48201 FAX: 313-577-7554 This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Wayne State University School of Medicine and the Journal of Clinical Outcomes Management. Wayne State University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Wayne State University School of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. 420 JCOM July 2007 Vol. 14, No. 7 www.turner-white.com