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Constipation often is regarded simply as a minor annoyance, but, in actuality, the disorder places a substantial burden on patients and society. In some cases, constipation is a temporary problem that can be self-treated. In other instances, however, it is a complex problem that requires the attention of a health care practitioner. Patients and health care practitioners often define constipation differently. Pharmacists are in an ideal position to help bridge this communication gap. This article will (1) provide an overview of the burden that constipation places on society; (2) differentiate key aspects of treatment options; and (3) assist pharmacists in determining when referral or further evaluation is necessary.
Constipation affects ~2% to 28% of the US population,1,2 particularly women, nonwhite persons, the elderly, and children.1,3-9 The large range in prevalence rates reflects variations in the definition of constipation and differences in study methodology. For many sufferers, this condition is chronic. In the 1991 National Health Interview Survey, 4.5 million Americans reported that they were constipated most or all of the time.3,10
Constipation can have a tremendous impact on patients' quality of life. Patients with constipation report significantly reduced general well-being and are more likely to describe symptoms of depression and anxiety, compared with the general population.11 The degree of impairment in quality of life increases as symptoms become more severe.11
Constipation is associated with a heavy socioeconomic burden. Reports suggest that, each year, 2.5 million physician visits, 100,000 referrals to gastroenterologists, and 92,000 hospitalizations in the United States can be attributed to constipation.1,12,13 Fees related to diagnostic testing and the cost of medications contribute substantially to this burden.8,9,13 Laxative sales alone are estimated to total more than $800 million a year.1,14
Indirect costs associated with this disorder also are substantial. Chronic constipation is estimated to account for 13.72 million days of restricted activity each year in the United States,8 potentially resulting in the need for time missed from work or leading to job loss.15
Constipation has different meanings for different people; no widely accepted and clinically meaningful definition for constipation currently exists.2,14,16 One study found that up to 50% of patients define constipation differently from physicians.9 Although most health care practitioners define constipation in terms of frequency of bowel movements (ie, fewer than 3 per week), patients incorporate other complaints into the definition, including hard stools, small stools, the need for digital manipulation, straining, feelings of incomplete evacuation, and abdominal bloating or pain.5,9,14,16,17 Patients list general malaise, abdominal swelling, abdominal pain, and nausea as the most disabling constipation-associated symptoms.15 For research purposes (ie, enrollment of patients into clinical trials), a consensus definition of constipation (Rome II diagnostic criteria) is used (Table 1).1,2,18
A formal distinction between temporary (acute, occasional) and chronic constipation has not been made. The term chronic constipation, however, usually refers to a disorder that has lasted for longer than 6 to 12 weeks 8,19 and has not responded within a reasonable time (eg, several days) to the use of simple dietary or therapeutic measures, such as fiber and over-the-counter (OTC) medications.1
Constipation may be attributed to primary or secondary causes (Table 2). Primary or idiopathic constipation refers to a condition for which there is no apparent external cause, or for which symptoms occur as the result of an intrinsic disorder of colonic motility and/or pelvic floor dysfunction.8,15,20 Primary constipation is typically divided into 3 main subtypes: normal-transit constipation, slow-transit constipation, and outlet obstruction or pelvic floor dysfunction.1,2,13,20,25,26
More than 1 mechanism may contribute to the constipation reported by an individual patient.1,13
In normal-transit constipation, the most common form of chronic constipation,1 stool transit time through the colon is normal, but patients have difficulty evacuating the stool, or they complain of hard stools.1 Some patients with normal-transit constipation fulfill the criteria for irritable bowel syndrome with constipation (IBS-C), a condition characterized by abdominal pain/discomfort and constipation.2,13,26 For the most part, abdominal pain as the primary complaint signals the presence of IBS-C.18,27 Straining, hard/lumpy stools, bloating/distention, and infrequent evacuation characterize chronic constipation.18,28
In slow-transit constipation, the movement of gastrointestinal (GI) contents from the proximal to the distal colon and rectum is slower than usual. This condition is most prevalent in young women.1,2,13,20 In patients with slow-transit constipation, the numbers of high-amplitude propagated contractions may be decreased and/or motor activity in the distal colon may be abnormal.2,13,25,29
Patients with outlet obstruction have prolonged storage of stool in the rectum caused by an inability to adequately evacuate the contents.13 Normal defecation requires coordination between the muscles involved in defecation (pelvic floor muscles) and rectal sensation.30 The most common cause of outlet obstruction is dysfunction of the pelvic floor muscles or the anal sphincter, known as pelvic floor dyssynergia.1,2
In contrast to primary causes, secondary causes of constipation involve various lifestyle choices, medical and psychological disorders, and medications (Table 2).3,4,13-15,21-24
When constipation is treated, the goals are to normalize bowel function and to alleviate all symptoms of the disorder.24,30 These treatment goals may be achieved through a variety of approaches, including education, lifestyle changes, pharmacologic therapy, behavioral therapy, and surgery.21,22
Managing Temporary Constipation
Many patients who come to the pharmacy seek relief from constipation that has existed for only a short time. This temporary form of constipation generally can be managed with education and lifestyle changes, as well as with the use of OTC medications.22
Education and Lifestyle Changes
Potentially beneficial lifestyle changes for temporary constipation, which can be considered before OTC medications are used, include increasing daily intake of dietary fiber, increasing fluid intake, and enhancing physical activity.21,22,24 Education (ie, regarding the importance of establishing regular bowel habits and promptly responding to the urge to defecate) is another critical aspect of care.2,19,21,22
An increase in daily dietary fiber may improve bowel function by adding bulk and softening the stool. The American Dietetic Association recommends ingestion of 20 to 30 g of dietary fiber per day. Various dietary sources are listed in Table 3.24 Of the foods listed, bran is the most effective laxative.22 Pharmacists should warn patients, however, that an increase in fiber may be poorly tolerated (ie, it may result in flatulence and abdominal discomfort, particularly during the first few weeks). Slowly increasing the amount of fiber in the diet may help reduce the likelihood of these adverse effects.22,24 An increase in dietary fiber should not be recommended for patients with fecal impaction, however, because fiber intake may worsen this condition.24
In patients with temporary constipation, pharmacologic therapy can be considered if lifestyle measures are not effective, or if more immediate relief is desired.24 Table 4 lists the wide variety of laxatives currently available on the market and provides information on their appropriate use. Because the mechanism of action of bulk-forming laxatives is similar to physiologic mechanisms, they are generally the laxatives of first choice.19-22,24,28 Bulk-forming laxatives primarily consist of natural polysaccharides (eg, psyllium) and semisynthetic or synthetic polysaccharides (methylcellulose and calcium polycarbophil, respectively).1,31 Because natural fiber undergoes bacterial degradation, its use often is associated with bloating and gas. In contrast, semisynthetic fiber is relatively resistant to degradation by colonic bacteria, and synthetic fiber is fully resistant to bacterial degradation. Consequently, both of the latter agents are better tolerated than is natural fiber (ie, they are less likely to cause bloating and gas).1
In patients who do not respond to bulk-forming laxatives, saline and hyperosmotic laxatives often are the next recommendation.19,22,28 Stimulant laxatives generally are reserved for patients who do not respond to lifestyle measures, fiber therapy, or saline or hyperosmotic therapy.19,21,22,28 Osmotic and stimulant laxatives often are used in preparation for GI procedures or surgery.20,24 When OTC stimulants are used, pharmacists should explain to patients that, if these stimulants fail to provide relief after a few days, patients should discontinue use and contact their health care practitioner. Even if relief is achieved with initial use, the return of constipation within a short time may signal the presence of a chronic condition for which the patient should be referred for further evaluation. Regular use of stimulant laxatives should be strongly discouraged. Emollient laxatives are useful for preventing constipation; however, they generally do not have a role in its treatment.21,24
The onset of action of laxatives varies widely; some laxatives work within hours, and others take days.24 Pharmacists should keep in mind that the manufacturers of most OTC laxatives recommend that these agents not be used for longer than 1 week without consultation with a health care practitioner.32 Because many patients with temporary constipation self-medicate,8,9 pharmacists should ask what medications have been tried before making any recommendations. When an OTC laxative is recommended, the maximum duration is an important counseling point 24 (Case Scenario 1).
Many patients use herbal products to treat constipation. In one study, 35% of patients with self-reported constipation had used a prescription, OTC, or herbal remedy during the previous year.33 Some herbal preparations commonly used for treating constipation are listed in Table 5. Patients should understand that herbal products are not reviewed or approved by the FDA, and that many questions regarding their efficacy and safety profiles remain unanswered.34 The potential for drug interactions and inconsistency in product quality are additional concerns.
Situations That Require Referral
Pharmacists may be asked for advice on how to manage constipation that has not responded to self-treatment. In handling this situation, the pharmacist must consider potential reasons behind the treatment failure. Some possibilities include an inappropriate drug choice, an inappropriate dosage regimen, unrealistic expectations from therapy (eg, a bowel movement every day), and the existence of a secondary cause of constipation (Table 2). Before making recommendations in this scenario, pharmacists should carefully question patients to determine potential reasons for the lack of response. If the pharmacist suspects a more serious health problem (based on the patient's description of "red flags" for organic disease [Table 6]), he or she should immediately refer the patient for further evaluation (Case Scenario 2).1,2,14,24,35,36
Managing Chronic Constipation
Unlike temporary constipation, which usually can be managed by self-treatment through lifestyle changes and/or the use of OTC agents, chronic constipation always requires referral to a health care practitioner. Treatments for chronic constipation include those used to treat temporary constipation, such as fiber, lifestyle measures, OTC and prescription medications, behavioral therapy, and surgery (reserved as a last resort for patients with disabling symptoms that are unresponsive to medical treatment). This article focuses on nonsurgical options. As has been mentioned, the type of treatment used varies according to the constipation subtype that is diagnosed.
Slow- or Normal-Transit Constipation
Traditional Treatment Options
Lifestyle Changes. As with temporary constipation, general lifestyle measures such as enhanced exercise and increased intake of fluid and dietary fiber are recommended for patients with slow- or normal-transit constipation.1,19,21,28 Data supporting the effectiveness of these measures in patients with chronic constipation are limited.2,19,37
Results of studies evaluating the effectiveness of enhanced exercise on the treatment of constipation are controversial. Some studies have found that regular exercise shortens gut transit time; others have demonstrated the opposite effect.2,37 In a recent study, Meshkinpour and colleagues 37 found that 4 weeks of regular moderate physical exercise did not alleviate slow-transit constipation.
Although increased fluid intake has been suggested for patients with chronic constipation, it is likely to be most beneficial for patients who are constipated at least in part because of dehydration.1 A small study of healthy volunteers demonstrated that consumption of extra fluid resulted in no significant increase in stool output.2 Large, controlled studies evaluating the effectiveness of increased fluid intake in chronically constipated patients have not been conducted.38 Consequently, it is probably best for pharmacists to tell patients to drink plenty of fluids without encouraging excessive hydration.2
Increased dietary fiber (up to 20-40 g per day) is recommended for patients with chronic constipation.1,19,21 A simple way to accomplish this increase is to exchange low-fiber foods for high-fiber foods (Table 3). Patients should be instructed to increase the amount of fiber in the diet slowly and to titrate this amount according to response.1,19 Because of the flatulence and bloating that may accompany this increase in fiber intake, compliance with a high-fiber diet generally is poor (as low as 50%).19,21,22
For patients who find it difficult to increase their dietary fiber intake, fiber supplements may be used.1,19 Flatulence and bloating with these agents, however, also may compromise compliance.1,13,19,26 Slow upward dose titration should be considered.8 As noted in Table 4, to avoid obstruction, adequate fluid intake is important when fiber supplements are taken.19
Laxatives. Patients with normal- or slow-transit chronic constipation who do not respond to lifestyle measures and increases in fiber may benefit from the use of laxatives.1,19,28 Saline, hyperosmotic, and (although limited) stimulant laxatives all play a role in the treatment of patients with chronic constipation.26,28 Generally, an osmotic laxative is tried first, followed by a stimulant laxative if the former is not effective.1 Because of the abuse potential (in both young and elderly patients), anecdotal evidence suggests that specialists generally should avoid prescribing regular use of stimulant laxatives. Further diagnostic testing or the use of other agents is preferred.
Efficacy data are limited and provide little assistance to the clinician who must decide which laxative to use for the treatment of chronic constipation. Numerous clinical studies have been published; however, many were poorly designed.8,39 Only a few published studies have compared laxatives (eg, polyethylene glycol [PEG], lactulose) with placebo, and most of these studies have described only short-term use.38-40 A recent meta-analysis found that, in studies of 4 weeks' duration or less, the efficacy of laxatives in patients with chronic constipation was only slightly better than placebo. In studies of 5 to 12 weeks' duration, no overall differences were demonstrated.39
As is shown in Table 4, the non?bulk-forming laxatives used for chronic constipation can be distinguished by their onset of activity, with oral hyperosmotic laxatives generally having a longer time of onset than oral saline or stimulant laxatives (which work within hours).13 Therefore, if a hyperosmotic laxative is prescribed, the pharmacist should be sure to explain to the patient that it may take several days to work, and that the patient should not be too quick to abandon therapy.1
Adverse effects associated with laxative use (eg, abdominal cramps and fecal incontinence, fluid and electrolyte disturbances)13 may be particularly troublesome with long-term use. Although many people fear that prolonged use of stimulant laxatives may result in the development of cathartic colon (ie, a degeneration of the enteric nerve pathways in the colon), most available data do not seem to support this fear.1,19,20,22,41 Because PEG is metabolically inert, its use is less likely to result in adverse effects, such as abdominal distention and flatulence, which are more likely with the use of agents such as lactulose and sorbitol.13,20 PEG electrolyte solutions (eg, GoLYTELY; Braintree Laboratories) are most often used for bowel cleansing performed before colonoscopy or bowel surgery. A formulation of PEG without electrolytes (PEG 3350 [MiraLax]; Braintree Laboratories) is indicated for short-term (<2 weeks) daily treatment of occasional constipation.42
Some patients with slow-transit constipation may benefit from the use of a promotility agent. Until recently (see Emerging Therapies), the use of drugs to promote colonic transit generally has proved disappointing. Cholinergic agents such as bethanechol have been tried with little success, and cisapride and metoclopramide appear to be ineffective in most constipated patients.20-22 Furthermore, in July of 2000, cisapride was removed from the market because of its association with potentially life-threatening cardiac arrhythmias.20 In cases of refractory constipation, drugs with promotility properties have been tried, including misoprostol (synthetic prostaglandin), colchicine, and erythromycin (motilin agonist).31,43-47 These agents should be used with caution, however. Misoprostol should not be used during pregnancy.48
Lack of Patient Satisfaction. Patient satisfaction with traditional treatment options for chronic constipation is generally low 15,19; adverse effects are an important contributing factor. Adverse effects have been reported to occur in 46% of patients who take laxatives.15 The use of bran supplements and adherence to a high-fiber diet have been reported to worsen symptoms in 80% of cases.15
New Therapy: Tegaserod
Recent evidence suggests that impaired GI motility and reduced intestinal secretion may play a role in the development of chronic constipation.20,25,29,49 The neurotransmitter serotonin (5-hydroxytryptamine [5-HT]), an important mediator of gut function, is likely to be involved in the pathogenesis of these abnormalities. Serotonin is an integral player in the enteric nervous system (ENS), a semi-autonomous system that organizes, coordinates, and processes the behavior patterns of the intestines, practically independently of the central nervous system (CNS). Serotonin mediates intestinal movement and intestinal secretion, modulates visceral sensation, and plays a key role in bidirectional communications between the ENS and the CNS.50-55
Tegaserod (Zelnorm; Novartis Pharmaceuticals) is a partial agonist at the 5-HT type 4 (5-HT4) receptor. This agent has been approved by the FDA for the short-term treatment of women with irritable bowel syndrome (IBS) whose primary bowel symptom is constipation (IBS-C) and, on August 20, 2004, for the treatment of men and women under 65 years old with chronic idiopathic constipation.56 The 3 main physiologic abnormalities involved in IBS-C include impaired GI motility, altered intestinal secretion, and visceral hypersensitivity.51 Tegaserod lessens symptoms of IBS-C by augmenting peristalsis, promoting intestinal secretion, and reducing visceral hypersensitivity.57-62 Well-designed pivotal clinical trials demonstrated that tegaserod was significantly more effective than placebo in providing global relief of IBS symptoms (the primary efficacy parameter), as well as in relieving single symptoms (eg, constipation, abdominal pain/discomfort) in women with IBS-C.63,64
In randomized clinical trials with IBS patients, serious consequences of diarrhea (eg, hypovolemia, hypotension, syncope, need for hospitalization) were rare, occurring in 0.04% of patients (4 in 10,000).56 The incidence of ischemic colitis (ie, a vascular condition caused by reduced blood flow to the colon, leading to colonic inflammation)65 in patients with IBS has been reported to be 4 to 5 times higher than in the general population.65,66 Although rare cases of ischemic colitis have been reported in patients taking tegaserod for IBS-C, the rate of these cases is consistent with that expected in the general population, and a causal relationship has not been established.56
Data from 2 large, double-blind, 12-week, placebo-controlled studies (1 conducted in North and South America and 1 in Europe, South Africa, and Australia) have demonstrated that tegaserod is useful for the treatment of patients with chronic constipation. In these studies, tegaserod was significantly more effective than placebo in increasing bowel movement frequency. It also provided rapid and sustained relief from the multiple symptoms of chronic constipation, including abdominal discomfort, bloating, straining, and abnormal stool consistency.67-70
Tegaserod has a favorable safety and tolerability profile. The most common adverse effect in the placebo-controlled chronic constipation trials was headache, which occurred in a lower percentage of patients receiving tegaserod 6 mg bid (9.8%-12.3%) than in patients receiving placebo (12.8%-13.7%).68-72 Although diarrhea was reported in these clinical trials, it was generally transient, rarely led to discontinuation of the medication, and usually resolved without rescue medication.69-72
A case report was recently published that described the occurrence of a mild myocardial infarction (MI) in a hospitalized patient with a history of MI, along with several other risk factors for MI, who was taking tegaserod as well as numerous other medications.73 Although tegaserod is designed to act as a potent 5-HT4 receptor agonist in the GI tract, it has moderate affinity for 5-HT1D and 5HT1B receptors. Because 5-HT1B receptor agonists (eg, sumatriptan) can have various deleterious effects on coronary arteries (eg, constriction, spasm),74 the authors hypothesized that tegaserod may have precipitated the MI that occurred during the patient's hospital stay via stimulation of 5-HT1D/5-HT1B receptors. Analysis of the pharmacologic, preclinical, clinical, and postmarketing data available to date, however, suggests no evidence of a causal relationship between tegaserod and cardiac events.75
Sodium Phosphate Monobasic Monohydrate and Sodium Phosphate and Sodium Dibasic Anhydrous. A combination of sodium phosphate monobasic monohydrate and sodium phosphate and sodium dibasic anhydrous (Visicol; InKine Pharmaceutical Company) is currently FDA-approved for cleansing of the bowel as a preparation for colonoscopy.76 A recent press release reported the results of a multicenter study that examined the use of this product in 40 patients with chronic constipation (published data not yet available). Patients were randomized to receive a 4- or 8-tablet regimen of this product for 4 weeks. Compared with baseline, both doses resulted in significant relief of constipation-associated symptoms. The 4-tablet regimen was not associated with statistically significant changes in mean blood electrolyte levels after 4 weeks of therapy. In the group of patients who received the 8-tablet regimen, a modest, but statistically significant, decrease in serum potassium was observed at the end of the study, compared with baseline. Further controlled studies designed to examine the use of this product in patients with constipation are planned.77
SPI-0211. SPI-0211 is a chloride channel activator that is currently in development for the treatment of several types of constipation. By activating specific chloride channels in the gut, SPI-0211 increases intestinal fluid chloride concentrations and intestinal fluid secretion.78 In 2 multicenter, double-blind, placebo-controlled studies with 3- to 4-week treatment phases, SPI-0211 was significantly more effective than placebo in providing relief from multiple symptoms of chronic constipation. The most common adverse effects reported were diarrhea, headache, and nausea.79-81 A randomized withdrawal study demonstrated that, after discontinuation of SPI-0211, no rebound constipation occurred.82
Outlet Obstruction (Pelvic Floor Dyssynergia)
Neuromuscular conditioning with biofeedback therapy plays a key role in the treatment of patients with pelvic floor dyssynergia, although some patients with this condition require the use of medications as well.19 During biofeedback therapy, patients receive auditory and/or visual feedback on the functioning of their anal sphincter and pelvic floor muscles. With biofeedback therapy, patients learn (1) how to relax their pelvic floor muscles during straining, and (2) how to coordinate abdominal maneuvers with relaxation to enhance the passage of stool into the rectum. Goals are to correct underlying dyssynergia and to improve rectal sensory perception.1,2,28
Biofeedback therapy may be useful for many patients with outlet obstruction due to pelvic floor dyssynergia (overall success rate of 67%).1 High-quality, controlled studies undertaken to evaluate this treatment approach are limited, however.1,83
Management of Constipation in Specific Patient Populations
The prevalence of chronic constipation among older patients (>65 years) has been estimated to be as high as 23% to 30%.8 Self-reported constipation affects up to 55% of chronically ill elderly patients in the community setting.84 With age-related physiologic changes and the high likelihood of comorbid chronic conditions and polypharmacy in these patients, the treatment of constipation in the elderly deserves special attention.24
To help minimize the likelihood of adverse events, the pharmacist who suggests a laxative for an older patient should check for comorbid medical conditions (via patient profile or questioning) and should find out which medications are being used for their treatment.24,85 Although bulk-forming laxatives often are used by older patients, these products should be used with caution because of the increased risk of intestinal obstruction if fluid intake is inadequate. Care must be taken to recommend a sugar-free product for patients with diabetes.
Other laxatives that have been recommended for use in the elderly include glycerin suppositories and oral sorbitol or lactulose. Because saline laxatives can cause shifts in fluid and electrolyte balance, their use should be avoided, particularly in patients with congestive heart failure. Because magnesium may be absorbed orally (resulting in toxicity), and given the likelihood of age-related renal insufficiency, laxatives containing magnesium should be used cautiously in older patients and in patients with established renal failure.85, 86
Long-term use of stimulant laxatives is not recommended for older patients because of the risk for laxative dependence. Because laxative preparations increase the rate at which drugs pass through the GI tract, the clinician must be careful to check whether a chosen treatment regimen interacts with any of the patient's active medications.24,84
Ideally, constipation in pregnancy is treated through dietary measures; drug therapy should be avoided whenever possible. Some women, however, require a laxative. Fiber supplements (along with plenty of fluids) generally are the preferred approach. Other options that appear to be safe during pregnancy include the prophylactic use of docusate, or the use of senna, bisacodyl, or lactulose for treatment. Use of certain laxatives should be avoided, however, because of adverse effects. For instance, mineral oil can decrease vitamin absorption, castor oil can cause premature labor, and saline laxatives can lead to electrolyte imbalances.20,24
Patients with Opioid-Induced Constipation
Up to 95% of patients who are receiving long-term opioid therapy report constipation.87 Consequently, it generally is recommended that patients begin a prophylactic bowel regimen upon treatment initiation (eg, the combination of a stool softener such as docusate sodium with a stimulant laxative such as senna).88,89 The use of bulk-forming laxatives in patients taking opioids is controversial. Some experts suggest that these products should not be used in this population because of an increased risk of intestinal obstruction. If bulk-forming laxatives are used in this setting, special attention must be paid to ensure adequate fluid intake.88,89
Pharmacists can play an important role in identifying and treating patients with temporary constipation. Understanding the key questions to ask and the situations that require referral is integral. Pharmacists also can counsel patients on the appropriate use of OTC and prescription medications for chronic constipation and can serve as the link between patients and health care practitioners.
Professor of Pharmacy, College of Pharmacy, The University of Michigan, Ann Arbor, Mich
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CE REVIEW QUESTIONS
(Based on the article starting on page 99.) Choose the 1 most correct answer.
1. Constipation is particularly prevalent in which of the following groups of people?
2. The usual onset of action of an oral laxative that contains senna is:
3. The use of which of the following types of medications is associated with an increased risk of constipation?
4. Tegaserod is a:
5. Which of the following is not a "red flag" for an organic disorder?
6. Which of the following statements regarding serotonin is false?
7. Lifestyle measures that may be useful for treating constipation include:
8. Foods high in fiber include all of the following except:
9. Patients define constipation as:
10. Which of the following medications works by increasing the wetting efficiency of intestinal fluid?
11. Which of the following is not an adverse effect associated with the use of bulk-forming laxatives?
12. Which of the following is the preferred laxative in pregnancy?
13. Which of the following agents is contraindicated in an elderly patient with congestive heart failure?
14. Neuromuscular conditioning with biofeedback often is useful in patients with:
15. Which of the following is not a common adverse effect reported with the use of SPI-0211?
16. Compared with healthy individuals, patients with constipation:
17. A patient with constipation should try to consume at least ____of dietary fiber each day.
18. If a patient with slow-transit constipation does not respond to lifestyle measures and fiber therapy, the next choice for treatment generally is:
19. Which of the following agents was withdrawn from the market because of its association with life-threatening arrhythmias?
20. Which of the following statements is false?