Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

23. Diarrhea, Constipation, and Irritable Bowel Syndrome

Patricia H. Fabel and Kayce M. Shealy


KEY CONCEPTS

 Images Diarrhea is caused by many viral and bacterial organisms. It is most often a minor discomfort, not life-threatening, and usually self-limited.

 Images The four pathophysiologic mechanisms of diarrhea have been linked to the four broad diarrheal groups, which are secretory, osmotic, exudative, and altered intestinal transit. The three mechanisms by which absorption occurs from the intestines are active transport, diffusion, and solvent drag.

 Images Management of diarrhea focuses on preventing excessive water and electrolyte losses, dietary care, relieving symptoms, treating curable causes, and treating secondary disorders.

 Images Bismuth subsalicylate is marketed for indigestion, relieving abdominal cramps, and controlling diarrhea, including traveler’s diarrhea, but may cause interactions with several components if given excessively.

 Images Constipation is defined as difficult or infrequent passage of stool, at times associated with straining or a feeling of incomplete defecation.

 Images Underlying causes of constipation should be identified when possible and corrective measures taken (e.g., alteration of diet or treatment of diseases such as hypothyroidism).

 Images The foundation of treatment of constipation is dietary fiber or bulk-forming laxatives that provide 20 to 25 g/day of raw fiber.

 Images Irritable bowel syndrome (IBS) is one of the most common GI disorders characterized by lower abdominal pain, disturbed defecation, and bloating. Many non-GI manifestations also exist with IBS. Visceral hypersensitivity is a major culprit in the pathophysiology of the disease.

 Images Diarrhea-predominant IBS should be managed by dietary modification and drugs such as loperamide when diet changes alone are insufficient to promote control of symptoms.

 Images Several drug classes are involved in the treatment of the pain associated with IBS including tricyclic compounds and the gut-selective calcium channel blockers.


DIARRHEA

Diarrhea is a troublesome discomfort that affects most individuals in the United States at some point in their lives and can be thought of as both a symptom and a sign. Usually diarrheal episodes begin abruptly and subside within 1 or 2 days without treatment. This chapter focuses primarily on noninfectious diarrhea, with only minor reference to infectious diarrhea (see Chap. 91 for a discussion of GI infections). Diarrhea is often a symptom of a systemic disease, and not all possible causes of diarrhea are discussed in this chapter. Acute diarrhea is commonly defined as <14 days’ duration, persistent diarrhea as >14 days’ duration, and chronic diarrhea as >30 days’ duration.

To understand diarrhea, one must have a reasonable definition of the condition; unfortunately, the literature is extremely variable on this. Simply put, diarrhea is an increased frequency and decreased consistency of fecal discharge as compared with an individual’s normal bowel pattern. Frequency and consistency are variable within and between individuals. For example, some individuals defecate as often as three times per day, whereas others defecate only two or three times per week. A Western diet usually produces a daily stool weighing between 100 and 300 g, depending on the amount of nonabsorbable materials (mainly carbohydrates) consumed. Patients with serious diarrhea may have a daily stool weight in excess of 300 g; however, a subset of patients experience frequent small, watery passages. Additionally, vegetable fiber-rich diets, such as those consumed in some Eastern cultures (e.g., those in Africa), produce stools weighing more than 300 g/day.

Diarrhea may be associated with a specific disease of the intestines or secondary to a disease outside the intestines. For instance, bacillary dysentery directly affects the gut, whereas diabetes mellitus causes neuropathic diarrheal episodes. Furthermore, diarrhea can be considered as acute or chronic disease. Infectious diarrhea is often acute; diabetic diarrhea is chronic. Congenital disorders in GI ion transport mechanisms are another cause of chronic diarrhea.1 Whether acute or chronic, diarrhea has the same pathophysiologic causes that help in identification of specific treatments.

Epidemiology

The epidemiology of diarrhea varies in developed versus developing countries.2 In the United States, diarrheal illnesses are usually not reported to the Centers for Disease Control and Prevention (CDC) unless associated with an outbreak or an unusual organism or condition. For example, the acquired immune deficiency syndrome (AIDS) has been identified with protracted diarrheal illness. Diarrhea is a major problem in daycare centers and nursing homes, probably because early childhood and senescence plus environmental conditions are risk factors. Although an exact epidemiologic profile in the United States is not available through the CDC or published literature, chronic diarrhea affects approximately 5% of the adult population and ranges from 3% to 20% in children worldwide.35 In developing countries, diarrhea is a leading cause of illness and death in children, creating a tremendous economic strain on healthcare costs.

Images Most cases of acute diarrhea are caused by infections with viruses, bacteria, or protozoa and are generally self-limited.6 Although viruses are more commonly associated with acute gastroenteritis, bacteria are responsible for more cases of acute diarrhea.

Evaluation of a noninfectious cause is considered if diarrhea persists and no infectious organism can be identified, or if the patient falls into a high-risk category for metabolic complications with persistent diarrhea. Common causative bacterial organisms include ShigellaSalmonellaCampylobacterStaphylococcus, and Escherichia coli. Foodborne bacterial infection is a major concern, as several major food poisoning episodes have occurred that were traced to poor sanitary conditions in meat processing plants. Acute viral infections are attributed mostly to the Norwalk and rotavirus groups.

Physiology

In the fasting state, 9 L of fluid enters the proximal small intestine each day. Of this fluid, 2 L is ingested through diet, while the remainder consists of internal secretions. Because of meal content, duodenal chyme is usually hypertonic. When chyme reaches the ileum, the osmolality adjusts to that of plasma, with most dietary fat, carbohydrate, and protein being absorbed. The volume of ileal chyme decreases to about 1 L/day on entering the colon, which is further reduced by colonic absorption to 100 mL daily. If the small intestine water absorption capacity is exceeded, chyme overloads the colon, resulting in diarrhea. In humans, the colon absorptive capacity is about 5 L daily. Colonic fluid transport is critical to water and electrolyte balance.

Absorption from the intestines back into the blood occurs by three mechanisms: active transport, diffusion, and solvent drag. Active transport and diffusion are the mechanisms of sodium transport. Because of the high luminal sodium concentration (142 mEq/L [142 mmol/L]), sodium diffuses from the sodium-rich gut into epithelial cells, where it is actively pumped into the blood and exchanged with chloride to maintain an isoelectric condition across the epithelial membrane.

Hydrogen ions are transported by an indirect mechanism in the upper small intestine. As sodium is absorbed, hydrogen ions are secreted into the gut. Hydrogen ions then combine with bicarbonate ions to form carbonic acid, which then dissociates into carbon dioxide and water. Carbon dioxide readily diffuses into the blood for expiration through the lung. The water remains in the chyme.

Paracellular pathways are major routes of ion movement. As ions, monosaccharides, and amino acids are actively transported, an osmotic pressure is created, drawing water and electrolytes across the intestinal wall. This pathway accounts for significant amounts of ion transport, especially sodium. Sodium plays an important role in stimulating glucose absorption. Glucose and amino acids are actively transported into the blood via a sodium-dependent cotransport mechanism. Cotransport absorption mechanisms of glucose–sodium and amino acid–sodium are extremely important for treating diarrhea.

Gut motility influences absorption and secretion. The amount of time in which luminal content is in contact with the epithelium is under neural and hormonal control. Neurohormonal substances, such as angiotensin, vasopressin, glucocorticoid, aldosterone, and neurotransmitters, also regulate ion transport.

Pathophysiology

Images Four general pathophysiologic mechanisms disrupt water and electrolyte balance, leading to diarrhea, and are the basis of diagnosis and therapy. These are (a) a change in active ion transport by either decreased sodium absorption or increased chloride secretion; (b) change in intestinal motility; (c) increase in luminal osmolarity; and (d) increase in tissue hydrostatic pressure. These mechanisms have been related to four broad clinical diarrheal groups: secretory, osmotic, exudative, and altered intestinal transit.

Secretory diarrhea occurs when a stimulating substance either increases secretion or decreases absorption of large amounts of water and electrolytes. Substances that cause excess secretion include vasoactive intestinal peptide (VIP) from a pancreatic tumor, unabsorbed dietary fat in steatorrhea, laxatives, hormones (such as secretion), bacterial toxins, and excessive bile salts. Many of these agents stimulate intracellular cyclic adenosine monophosphate and inhibit Na+/K+-adenosine triphosphatase (ATPase), leading to increased secretion. Also, many of these mediators inhibit ion absorption simultaneously. Secretory diarrhea is recognized by large stool volumes (>1 L/day) with normal ionic contents and osmolality approximately equal to plasma. Fasting does not alter the stool volume in these patients.

Poorly absorbed substances retain intestinal fluids, resulting in osmotic diarrhea. This process occurs with malabsorption syndromes, lactose intolerance, administration of divalent ions (e.g., magnesium-containing antacids), or consumption of poorly soluble carbohydrate (e.g., lactulose). As a poorly soluble solute is transported, the gut adjusts the osmolality to that of plasma; in so doing, water and electrolytes flux into the lumen. Clinically, osmotic diarrhea is distinguishable from other types, as it ceases if the patient resorts to a fasting state.

Inflammatory diseases of the GI tract discharge mucus, serum proteins, and blood into the gut. Sometimes bowel movements consist only of mucus, exudate, and blood. Exudative diarrhea affects other absorptive, secretory, or motility functions to account for the large stool volume associated with this disorder.

Altered intestinal motility produces diarrhea by three mechanisms: reduction of contact time in the small intestine, premature emptying of the colon, and bacterial overgrowth. Chyme must be exposed to intestinal epithelium for a sufficient time period to enable normal absorption and secretion processes to occur. If this contact time decreases, diarrhea results. Intestinal resection or bypass surgery and drugs (such as metoclopramide) cause this type of diarrhea. On the other hand, an increased time of exposure allows fecal bacteria overgrowth. A characteristic small intestine diarrheal pattern is rapid, small, coupling bursts of waves. These waves are inefficient, do not allow absorption, and rapidly dump chyme into the colon. Once in the colon, chyme exceeds the colonic capability to absorb water.

Etiologic Examination of the Stool

Stool characteristics are important in assessing the etiology of diarrhea. A description of the frequency, volume, consistency, and color provides diagnostic clues. For instance, diarrhea starting in the small intestine produces a copious, watery or fatty (greasy), and foul-smelling stool; contains undigested food particles; and is usually free from gross blood. Colonic diarrhea appears as small, pasty, and sometimes bloody or mucoid movements. Rectal tenesmus with flatus accompanies large intestinal diarrhea.

Clinical Presentation

Table 23-1 outlines the clinical presentation of diarrhea, and Table 23-2 shows common drug-induced causes of diarrhea. A medication history is extremely important in identifying drug-induced diarrhea. Many agents, including antibiotics and other drugs, cause diarrhea or, less commonly, pseudomembranous colitis. Self-inflicted laxative abuse for weight loss is popular.

TABLE 23-1 Clinical Presentation of Diarrhea

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TABLE 23-2 Drugs Causing Diarrhea

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Most acute diarrhea is self-limiting, subsiding within 72 hours. However, infants, young children, the elderly, and debilitated persons are at risk for morbid and mortal events in prolonged or voluminous diarrhea. These groups are at risk for water, electrolyte, and acid–base disturbances, and potentially cardiovascular collapse and death. The prognosis for chronic diarrhea depends on the cause; for example, diarrhea secondary to diabetes mellitus waxes and wanes throughout life.

TREATMENT

Prevention

Acute viral diarrheal illness often occurs in daycare centers and nursing homes. Because person-to-person contact is the mechanism by which viral disease spreads, isolation techniques must be initiated. For bacterial, parasitic, and protozoal infections, strict food handling, sanitation, water, and other environmental hygiene practices can prevent transmission. If diarrhea is secondary to another illness, controlling the primary condition is necessary. Antibiotics and bismuth subsalicylate are advocated to prevent traveler’s diarrhea, in conjunction with treatment of drinking water and caution with consumption of fresh vegetables.7

Desired Outcome

Images If prevention is unsuccessful and diarrhea occurs, therapeutic goals are to (a) manage the diet; (b) prevent excessive water, electrolyte, and acid–base disturbances; (c) provide symptomatic relief; (d) treat curable causes; and (e) manage secondary disorders causing diarrhea (Figs. 23-1 and 23-2).

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FIGURE 23-1 Recommendations for treating acute diarrhea. Follow the following steps: (a) Perform a complete history and physical examination. (b) Is the diarrhea acute or chronic? If chronic diarrhea, go to Figure 23-2. (c) If acute diarrhea, check for fever and/or systemic signs and symptoms (i.e., toxic patient). If systemic illness (fever, anorexia, or volume depletion), check for an infectious source. If positive for infectious diarrhea, use appropriate antibiotic/anthelmintic drug and symptomatic therapy. If negative for infectious cause, use only symptomatic treatment. (d) If no systemic findings, then use symptomatic therapy based on severity of volume depletion, oral or parenteral fluid/electrolytes, antidiarrheal agents (see Table 23-4), and diet. (RBC, red blood cells; WBC, white blood cells.)

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FIGURE 23-2 Recommendations for treating chronic diarrhea. Follow the following steps: (a) Perform a careful history and physical examination. (b) The possible causes of chronic diarrhea are many. These can be classified into intestinal infections (bacterial or protozoal), inflammatory disease (Crohn’s disease or ulcerative colitis), malabsorption (lactose intolerance), secretory hormonal tumor (intestinal carcinoid tumor or vasoactive intestinal peptide-secreting tumor [VIPoma]), drug (antacid), factitious (laxative abuse), or motility disturbance (diabetes mellitus, irritable bowel syndrome, or hyperthyroidism). (c) If the diagnosis is uncertain, selected appropriate diagnostic studies should be ordered. (d) Once diagnosed, treatment is planned for the underlying cause with symptomatic antidiarrheal therapy. (e) If no specific cause can be identified, symptomatic therapy is prescribed. (RBC, red blood cells; WBC, white blood cells.)

Clinicians must clearly understand that diarrhea, like a cough, may be a body defense mechanism for ridding itself of harmful substances or pathogens. The correct therapeutic response is not necessarily to stop diarrhea at all costs.

Nonpharmacologic Management

Dietary management is a first priority in the treatment of diarrhea. Most clinicians recommend discontinuing consumption of solid foods and dairy products for 24 hours. However, fasting is of questionable value, as this treatment modality has not been extensively studied. In osmotic diarrhea, these maneuvers control the problem. If the mechanism is secretory, diarrhea persists. For patients who are experiencing nausea and/or vomiting, a mild, digestible, low-residue diet should be administered for 24 hours. If vomiting is present and uncontrollable with antiemetics (see Chap. 22), nothing is taken by mouth. As bowel movements decrease, a bland diet is begun.

Feeding should continue in children with acute bacterial diarrhea. Fed children have less morbidity and mortality, whether or not they receive oral rehydration fluids. Studies are not available in the elderly or in other high-risk groups to determine the value of continued feeding in bacterial diarrhea.

Water and Electrolytes

Rehydration and maintenance of water and electrolytes are primary treatment goals until the diarrheal episode ends. If the patient is volume depleted, rehydration should be directed at replacing water and electrolytes to normal body composition. Then water and electrolyte composition are maintained by replacing losses. Many patients will not develop volume depletion and therefore will only require maintenance fluid and electrolyte therapy. Parenteral and enteral routes may be used for supplying water and electrolytes. If vomiting and dehydration are not severe, enteral feeding is the less costly and preferred method. In the United States, many commercial oral rehydration preparations are available (Table 23-3).

TABLE 23-3 Oral Rehydration Solutions

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Because of concerns about hypernatremia, physicians continue to hospitalize patients and use IV fluids to correct fluid and electrolyte deficits in severe dehydration. Oral solutions are strongly recommended.810 In developing countries, the World Health Organization oral rehydration solution (WHO-ORS) saves the lives of millions of children annually.

During diarrhea, the small intestine retains its ability to actively transport monosaccharides such as glucose. Glucose actively carries sodium with water and other electrolytes. The WHO now recommends an ORS with a lower osmolarity, sodium content, and glucose load (see Table 23-3).11 A separate oral supplement of zinc 20 mg daily for 14 days in addition to ORS significantly reduces the severity and duration of acute diarrhea in developing countries.8,12 ORS is a lifesaving treatment for millions afflicted in developing countries. Acceptance in developed countries is less enthusiastic; however, the advantage of this product in reducing hospitalizations may prove its use as a cost-effective alternative, saving millions of dollars in healthcare expenditures.

Pharmacologic Therapy

Various drugs have been used to treat diarrheal attacks (Table 23-4), including antimotility agents, adsorbents, antisecretory compounds, antibiotics, enzymes, and intestinal microflora. Usually these drugs are not curative but palliative.

TABLE 23-4 Selected Antidiarrheal Preparations

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Opiates and Their Derivatives

Opiates and opioid derivatives (a) delay the transit of intraluminal contents or (b) increase gut capacity, prolonging contact and absorption. Enkephalins, which are endogenous opioid substances, regulate fluid movement across the mucosa by stimulating absorptive processes. Limitations to the use of opiates include an addiction potential (a real concern with long-term use) and worsening of diarrhea in selected infectious diarrhea.

Most opiates act through peripheral and central mechanisms with the exception of loperamide, which acts only peripherally. Loperamide is antisecretory; it inhibits the calcium-binding protein calmodulin, controlling chloride secretion. Loperamide, available as 2 mg capsules or 1 mg/5 mL solution (both are nonprescription products), is suggested for managing acute and chronic diarrhea. The usual adult dose is initially 4 mg orally, followed by 2 mg after each loose stool, up to 16 mg/day. Used correctly, this agent has rare side effects, such as dizziness and constipation. If the diarrhea is concurrent with a high fever or bloody stool, the patient should be referred to a physician. Also, diarrhea lasting 48 hours beyond initiating loperamide warrants medical attention. Loperamide can also be used in traveler’s diarrhea. It is comparable to bismuth subsalicylate for treatment of this disorder.7

Diphenoxylate is available as a 2.5 mg tablet and as a 2.5 mg/5 mL solution. A small amount of atropine (0.025 mg) is included in the product to discourage abuse. In adults, when taken as 2.5 to 5 mg three or four times daily, not to exceed a 20 mg total daily dose, diphenoxylate is rarely toxic. Some patients may complain of atropinism (blurred vision, dry mouth, and urinary hesitancy). Like loperamide, it should not be used in patients who are at risk of bacterial enteritis with E. coliShigella, or Salmonella.

Difenoxin, a diphenoxylate derivative also chemically related to meperidine, is also combined with atropine and has the same uses, precautions, and side effects. Marketed as a 1 mg tablet, the adult dosage is 2 mg initially, followed by 1 mg after each loose stool, not to exceed 8 mg/day.

Paregoric, camphorated tincture of opium, is marketed as a 2 mg/5 mL solution and is indicated for managing both acute and chronic diarrhea. It is not widely prescribed today because of its abuse potential.


Clinical Controversy…

Long-term use of oral opiates is not routinely recommended for several pharmacologic reasons. Some opioids such as morphine and codeine have the tendency to cause constipation by slowing down the peristaltic action of the bowels, which can also result in a functional ileus. This effect can be minimized by administering laxatives and/or stool softeners in patients who require long-term opiate therapy. Prokinetic agents may also be helpful in treating opiate-related constipation.

Adsorbents

Adsorbents are used for symptomatic relief. These products, many not requiring a prescription, are nontoxic, but their effectiveness remains unproven. Adsorbents are nonspecific in their action; they adsorb nutrients, toxins, drugs, and digestive juices. Polycarbophil absorbs 60 times its weight in water and can be used to treat both diarrhea and constipation. It is a nonprescription product and is sold as a 500 mg chewable tablet. This hydrophilic, nonabsorbable product is safe and may be taken four times daily, up to 6 g/day in adults. See Table 23-4 for selected antidiarrheal preparations.

Antisecretory Agents

Bismuth subsalicylate appears to have antisecretory, antiinflammatory, and antibacterial effects. As a nonprescription product, it is marketed for indigestion, relieving abdominal cramps, and controlling diarrhea, including traveler’s diarrhea. Bismuth subsalicylate dosage strengths are a 262 mg chewable tablet, 262 mg/5 mL liquid, and 524 mg/15 mL liquid. The usual adult dose is two tablets or 30 mL every 30 minutes to 1 hour up to eight doses per day.

Images Bismuth subsalicylate contains multiple components that might be toxic if given excessively to prevent or treat diarrhea. For instance, an active ingredient is salicylate, which may interact with anticoagulants or may produce salicylism (tinnitus, nausea, and vomiting). Bismuth reduces tetracycline absorption and may interfere with select GI radiographic studies. Patients may complain of a darkening of the tongue and stools with repeat administration. Salicylate can induce gout attacks in susceptible individuals.

Bismuth subsalicylate suspension has been evaluated in the treatment of secretory diarrhea of infectious etiology as well. In a dose of 30 mL every 30 minutes for eight doses, unformed stools decrease in the first 24 hours. Bismuth subsalicylate may also be effective in preventing traveler’s diarrhea.

Octreotide, a synthetic octapeptide analog of endogenous somatostatin, is effective for the symptomatic treatment of carcinoid tumors and other peptide-secreting tumors, dumping syndrome, and chemotherapy-induced diarrhea.13 It has had limited success in patients with AIDS-associated diarrhea and short-bowel syndrome, does not appear to have an advantage over various opiate derivatives in the treatment of chronic idiopathic diarrhea, and has the disadvantage of being administered by injection.14 Metastatic intestinal carcinoid tumors secrete excessive amounts of vasoactive substances, including histamine, bradykinin, serotonin (5-HT), and prostaglandins. Primary carcinoid tumors occur throughout the GI tract, with most in the ileum. Predominant signs and symptoms experienced by patients with these tumors are attributable to excessive concentrations of 5-hydroxytryptophan and 5-HT. The totality of their clinical effects is termed the carcinoid syndrome. Some patients have a violent, watery diarrhea with abdominal cramping. Initially, diarrhea might be managed with various agents such as codeine, diphenoxylate, cyproheptadine, methysergide, phenoxybenzamine, or methyldopa. But octreotide is now considered first-line therapy for carcinoid syndrome.

Octreotide blocks the release of 5-HT and many other active peptides and has been effective in controlling diarrhea and flushing. It is reported to have direct inhibitory effects on intestinal secretion and stimulatory effects on intestinal absorption. Non–gastrin-secreting adenomas of the pancreas are tumors associated with profuse watery diarrhea. This condition has been referred to as Verner-Morrison syndrome, WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, pancreatic cholera, watery diarrhea syndrome, and vasoactive intestinal peptide-secreting tumor (VIPoma). Excessive secretion of VIP from a retroperitoneal or pancreatic tumor produces most of the clinical features. Surgical tumor dissection is the treatment of choice. In nonsurgical candidates, the profuse watery diarrhea and other symptoms commonly encountered are managed with octreotide.

The dose of octreotide varies with the indication, disease severity, and patient response.13 For managing diarrhea and flushing associated with carcinoid tumors in adults, the initial dosage range is 100 to 600 mcg/day in two to four divided doses subcutaneously for 2 weeks. For controlling secretory diarrhea of VIPomas, the dosage range is 200 to 300 mcg/day in two to four divided doses for 2 weeks. Some patients may require higher doses for symptomatic control. Patients responding to these initial doses may be switched to Sandostatin LAR Depot, a long-acting octreotide formulation. This product consists of microspheres containing the drug. Initial doses consist of 20 mg given intramuscularly intragluteally at 4-week intervals for 2 months. It is recommended that during the first 2 weeks of therapy the short-acting formulation also be administered subcutaneously. At the end of 2 months, patients with good symptom control may have the dose reduced to 10 mg every 4 weeks, while those without sufficient symptom control may have the dose increased to 30 mg every 4 weeks. For patients experiencing recurrence of symptoms on the 10 mg dose, dosage adjustment to 20 mg should be made. It is not uncommon for patients with carcinoid tumors or VIPomas to experience periodic exacerbation of symptoms. Subcutaneous octreotide for several days should be reinstituted in these individuals. In so-called carcinoid crisis, octreotide is given as an IV infusion at 50 mcg/h for 8 to 24 hours.

Because octreotide inhibits many other GI hormones, it has a variety of intestinal side effects. With prolonged use, gallbladder and biliary tract complications such as cholelithiasis have been reported. Approximately 5% to 10% of patients complain of nausea, diarrhea, and abdominal pain. Local injection pain occurs with about an 8% incidence. With high doses, octreotide may reduce dietary fat absorption, leading to steatorrhea.

Two other somatostatin analogs, lanreotide and vapreotide, have been studied.14,15 Lanreotide is approved for use in the United States for acromegaly. The starting dose is 90 mg subcutaneously every 4 weeks for 3 months, and then the dose is adjusted based on growth hormone and insulin-like growth factor levels.16 Vapreotide is an orphan drug that is indicated for pancreatic and GI fistulas as well as esophageal variceal bleeding.

Miscellaneous Products

Probiotics are microorganisms that have been used for many years to replace colonic microflora. This supposedly restores normal intestinal function and suppresses the growth of pathogenic microorganisms. Saccharomyces boulardiiLactobacillus GG, and Lactobacillus acidophilus decrease the duration of infectious and antibiotic-induced diarrhea in adults and children.17 A combination probiotic product, VSL#3 (which contains multiple strains of lactobacilli and bifidobacteria) may have benefit in preventing radiation-induced diarrhea when given three times a day.18 A meta-analysis suggests that probiotics may prevent antibiotic-associated diarrhea (AAD).19 The dosage of probiotic preparations varies depending on the brand used. Intestinal flatus is the primary patient complaint experienced with this modality.

Anticholinergic drugs such as atropine block vagal tone and prolong gut transit time. Drugs with anticholinergic properties are present in many nonprescription products. Their value in controlling diarrhea is questionable and limited because of side effects. Angle-closure glaucoma, selected heart diseases, and obstructive uropathies are relative contraindications to the use of anticholinergic agents.

Lactase enzyme products are helpful for patients who are experiencing diarrhea secondary to lactose intolerance. Lactase is required for carbohydrate digestion. When a patient lacks this enzyme, eating dairy products causes an osmotic diarrhea. Several products are available for use each time a dairy product, especially milk or ice cream, is consumed.


Clinical Controversy…

The use of probiotics to treat and prevent AAD is controversial. A meta-analysis published in 2012 concluded that adjunctive probiotics significantly reduce the risk of acquiring AAD, but individual studies have been unclear as to whether there is any benefit. Additional studies are needed to compare different probiotic formulations, determine optimal dosing, and evaluate whether efficacy differs based on the antibiotic used. Additional safety data are also required before probiotics can be recommended routinely for this purpose.

Investigational Drugs

Several new classes of compounds are undergoing clinical trials for efficacy in acute diarrhea. Enkephalins are endogenous opiate compounds in the gut that have antisecretory and proabsorptive activity in the small intestine. They promote sodium and chloride reabsorption via stimulation of a nonadrenergic, noncholinergic neurotransmitter. Enkephalinase inhibitors are compounds that slow down the enzymatic (i.e., enkephalinase) breakdown of endogenous enkephalins found in the small intestines. They exert an antisecretory effect without affecting GI motility or CNS-related effects/side effects. One specific compound, originally called acetorphan but now referred to as racecadotril, has been extensively tested in humans and found to be equal to other opiate antidiarrheals such as loperamide, while causing less GI motility side effects such as abdominal bloating, pain, and constipation.2022 Racecadotril is currently licensed only in France and a few developing countries with a high incidence of childhood diarrhea.

Vaccines are a new therapeutic frontier in controlling infectious diarrheas, especially in developing countries.23,24 An oral vaccine for cholera is licensed and available in other countries (Dukoral from SBL Vaccines) and appears to provide somewhat better immunity and has fewer adverse effects than the previously available parenteral vaccine. However, the CDC does not recommend cholera vaccines for most travelers, nor is the vaccine available in the United States.

Oral Shigella vaccine, although effective under field conditions, requires five weekly oral doses and repeat booster doses, thereby limiting its practicality for use in developing nations. With about 1,500 serotypes for Salmonella, a vaccine is not currently available for humans. There are two newer typhoid vaccine formulations, one a parenteral inactivated whole-cell vaccine and the other an oral live-attenuated (Ty21a) vaccine that is administered in four doses on days 1, 3, 5, and 7, to be completed at least 1 week before exposure. Two rotavirus vaccines have been shown to prevent gastroenteritis due to rotavirus infection in infants and children.25 The pentavalent human-bovine reassortant vaccine (RotaTeq from Merck) is administered as a three-oral-dose sequence, and the monovalent human vaccine (Rotarix from GlaxoSmithKline) is administered as a two-oral-dose sequence. A rotavirus vaccine program has been formed to reduce child morbidity and mortality from diarrheal disease by accelerating the availability of rotavirus vaccines appropriate for use in developing countries.

Evaluation of Therapeutic Outcomes

Therapeutic outcomes are directed toward key symptoms, signs, and laboratory studies. Constitutional symptoms usually improve within 24 to 72 hours. Monitoring for changes in the frequency and character of bowel movements on a daily basis in conjunction with vital signs and improvement in appetite are of utmost importance. Also, the clinician needs to monitor body weight, serum osmolality, serum electrolytes, complete blood cell counts, urinalysis, and culture results (if appropriate).

Acute Diarrhea

Most patients with acute diarrhea experience mild to moderate distress. In the absence of moderate to severe dehydration, high fever, and blood or mucus in the stool, this illness is usually self-limiting within 3 to 7 days. Mild to moderate acute diarrhea is usually managed on an outpatient basis with oral rehydration, symptomatic treatment, and diet. Elderly persons with chronic illness as well as infants may require hospitalization for parenteral rehydration and close monitoring.

Severe Diarrhea

In the urgent/emergent situation, restoration of the patient’s volume status is the most important outcome. Toxic patients (fever dehydration, hematochezia, or hypotension) require hospitalization, IV fluids and electrolyte administration, and empiric antibiotic therapy while awaiting culture and sensitivity results. With timely management, these patients usually recover within a few days.

CONSTIPATION

Images Constipation is a common complaint among the general population and accounts for many medical visits each year in the United States.26 It is generally defined by the American Gastroenterology Association (AGA) as difficult or infrequent passage of stool, at times associated with straining or a feeling of incomplete defecation.27

Constipation may be further defined by quantitative or qualitative measures. For instance, physicians often use stool frequency to define constipation (most commonly fewer than three bowel movements per week); however, the “normal” frequency of bowel movement is not well established and can vary from person to person. Patients more often describe constipation in terms of symptoms or a combination of quantitative and qualitative descriptors that are difficult to quantify: bowel movement frequency, stool size or consistency (hard or lumpy stools), straining on defecation, inability to defecate at will, and symptoms such as sensation of incomplete evacuation. The condition is considered chronic if symptoms last for at least 3 months. Many people believe that daily bowel movements are required for normal health or that accumulation of toxic substances will occur with infrequent defecation. Inappropriate laxative use by the general public may result from these misconceptions.

Though often considered more of a minor uncomfortable or unpleasant problem, constipation can have serious consequences and be costly to the healthcare system. Costs for medical evaluation of constipation alone have been estimated at more than $2,500 per patient, and patients spend more than an estimated $800 million each year on nonprescription laxatives.26,28

Epidemiology

The prevalence of constipation depends on the definition used and whether the condition is self-reported or provider-diagnosed. A systematic review of 45 studies reported the prevalence of chronic constipation in adults (≥15 years old) worldwide to be 14%.27 The highest incidence was found in South America (16%) and the lowest incidence in Southeast Asia. A review of the epidemiology of constipation in North America specifically found a prevalence for constipation up to 27%, with most reported estimates ranging from 12% to 19%.29 Similarly, in a multinational survey of 13,879 adult participants from seven countries, the rate of self-reported constipation was 12.3% overall (range 5% to 18%).29,30

Constipation is more common in women (2.4-fold more likely) and the elderly.27 Other factors associated with constipation in some reports include inactivity, lower socioeconomic class, lower income, non-white race, symptoms of depression, and history of physical or sexual abuse.

Pathophysiology

Constipation may be primary or secondary. Primary, or idiopathic, constipation occurs without an identifiable underlying cause, whereas secondary constipation may be the result of constipating drugs, lifestyle factors, or medical disorders (Table 23-5).31 Primary constipation can be further divided into three categories—functional, slow transit, and outlet dysfunction, or disordered defecation. Functional constipation, often referred to as normal transit, is the most common type. These patients have normal GI motility and stool frequency but may experience difficulty evacuating, passage of hard stools, or bloating and abdominal discomfort. Slow transit constipation represents an abnormality of GI transit time that leads to infrequent defecation. Dysfunction of the pelvic floor muscles and/or anal sphincter is the most frequently encountered reason for disordered defecation. In patients with defecatory disorders, these muscles or sphincter contract during defecation instead of relax and impede evacuation of stool. It is common for patients to have and present with more than one type of constipation.

TABLE 23-5 Possible Causes of Constipation

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Factors associated with the increased prevalence of constipation in the elderly include a higher number of daily medications, particularly anticholinergic agents, increased incidence of chronic comorbidities, and changes in mobility status.28 Changes in diet such as decreased fluid and/or fiber intake, diminished physical activity, and institutionalization can lead to constipation. Physiologic changes such as mesenteric dysfunction and changes in anorectal function, including loss of rectal wall elasticity, are also thought to predispose elderly patients to constipation.

Drug-Induced Constipation

Use of drugs that inhibit the neurologic or muscular function of the GI tract, particularly the colon, may result in secondary constipation.31 Medications that are commonly associated with causing constipation include opiates, anticholinergic agents, and certain antacids.28 With most of the agents listed in Table 23-6, the inhibitory effects on bowel function may be dose dependent, with larger doses causing constipation more frequently.

TABLE 23-6 Drugs Causing Constipation

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Opiates have effects on all segments of the bowel, but effects are most pronounced on the colon.27 The major mechanism by which opiates produce constipation has been proposed to be prolongation of intestinal transit time by causing spastic, nonpropulsive contractions. An additional contributory mechanism may be an increase in electrolyte absorption.

While all opiate derivatives are associated with constipation, the degree of intestinal inhibitory effects seems to differ between agents. Orally administered opiates appear to have greater inhibitory effects than parenterally administered products. In some reports, transdermal fentanyl has been associated with less constipation than oral sustained-release morphine.32

Other medications may increase the risk of constipation by a variety of mechanisms. Anticholinergic agents decrease contractility of intestinal muscle while calcium channel blockers are thought to cause rectosigmoid dysfunction, leading to constipation. Nonsteroidal antiinflammatory drugs (NSAIDs) may lead to constipation due to their inhibition of prostaglandin synthesis.28

Clinical Presentation

A symptom-based system for classifying functional constipation (and other functional GI disorders) is often used to define constipation in clinical trials. The Rome criteria encompass both quantitative (frequency) and qualitative (stool consistency, etc.) symptoms associated with constipation.33 Table 23-7 outlines general clinical presentation of patients with constipation. According to the Rome III criteria, patients should have at least 2 of the signs and symptoms listed in Table 23-7 apply to a minimum of 25% of bowel movements.

TABLE 23-7 Clinical Presentation of Constipation

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Evaluation of constipation should attempt to clarify the patient’s specific symptoms (i.e., exactly what the patient means by constipation).33 A complete and thorough history should be obtained from the patient, including frequency of bowel movements and duration of symptoms. Constipation occurring abruptly in an adult may indicate significant colon pathology such as malignancy. Constipation present since early infancy may be indicative of neurologic disorders. The patient should also be carefully questioned about usual diet and laxative regimens. Does the patient have a diet consistently deficient in high-fiber items and containing mainly high refined foods? What laxatives or cathartics has the patient used to attempt relief of constipation? The patient should be questioned about other concurrent medications, with interest focused on agents that might cause constipation.

Evaluation should also include perianal and anal examinations to identify fecal impaction or other anatomical obstructions that may be contributing to or causing constipation. General health status, signs of underlying medical illness (i.e., hypothyroidism), and psychological status (e.g., depression or other psychological illness) should also be assessed. Laboratory tests may be performed, particularly if the patient is presumed to suffer from secondary causes.

Specific attention should be given to identify any “alarm symptoms” that would warrant further diagnostic workup (see Table 23-7).34 Patients with alarm symptoms, a family history of colon cancer, or those >50 years old with new symptoms may need further diagnostic evaluation.

TREATMENT

Desired Outcome

The major goals of treatment are to (a) relieve symptoms; (b) reestablish normal bowel habits; and (c) improve quality of life by minimizing adverse effects of treatment.

General Approach to Treatment

Table 23-8 presents a general treatment algorithm for the management of constipation.

TABLE 23-8 Constipation Treatment Algorithm

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Images Approaches to the treatment of constipation should begin with attempts to determine its cause. If an underlying disease is recognized as the cause of constipation, attempts should be made to correct it. GI malignancies may be removed via surgical resection. Endocrine and metabolic derangements should be corrected by the appropriate methods. For example, when hypothyroidism is the cause of constipation, cautious institution of thyroid replacement therapy is the most important treatment measure.

As discussed earlier, many drug substances may cause constipation. If a patient is consuming medications known to cause constipation, consideration should be given to alternative agents. If no reasonable alternatives exist to the medication thought to be responsible for constipation, consideration should be given to lowering the dose. If a patient must remain on constipating medications, then more attention must be given to general measures for prevention of constipation, as discussed in the next section.

The proper management of constipation will require a combination of nonpharmacologic and pharmacologic therapies. Laxative therapy is considered the preferred first line for the treatment of constipation, in addition to increasing dietary fiber. Patients are often encouraged to increase daily fluid intake and physical activity as well dedicate time to respond to the urge to defecate, although efficacy data are conflicting for these measures.35

Nonpharmacologic Therapy

Dietary Modification

The most important aspect of therapy for constipation for the majority of patients is dietary modification to increase the amount of fiber consumed. Fiber, the portion of vegetable matter not digested in the human GI tract, increases stool bulk, retention of stool water, and rate of transit of stool through the intestine. The result of fiber therapy is an increased frequency of defecation. Also, fiber decreases intraluminal pressures in the colon and rectum, which is thought to be beneficial for diverticular disease and for irritable bowel syndrome (IBS).

Images The specific physiologic effects of fiber are not well understood. Patients should be advised to gradually increase daily fiber intake to 20 to 25 g, through either dietary changes or fiber supplement products (see Bulk-Forming Agents below), a grade B recommendation from the American College of Gastroenterology.36 Fruits, vegetables, and cereals typically have the highest fiber content. Bran, a by-product of milling of wheat, is often added to foods to increase fiber content and contains a high amount of soluble fiber, which may be extremely constipating in larger doses. Raw bran is generally 40% fiber. A small randomized controlled trial revealed that adding prunes (approximately 6 g fiber/day), or dried plums, to daily diet was more effective than adding psyllium (6 g fiber/day) in treating mild to moderate constipation.37

A trial of dietary modification with high-fiber content should be continued for at least 1 month before effects on bowel function are determined. Most patients begin to notice effects on bowel function 3 to 5 days after beginning a high-fiber diet, but some patients may require a considerably longer period of time. Patients should be cautioned that abdominal distension and flatulence may be particularly troublesome in the first few weeks of fiber therapy, particularly with high bran consumption. Gradually increasing dietary fiber over a few weeks to the goal of 20 to 25 g may help reduce some of the adverse abdominal effects. In most cases these problems resolve with continued use.

Surgery

In a small percentage of patients who present with complaints of constipation, surgical procedures are necessary because of the presence of colonic malignancies or GI obstruction from a number of other causes. Patients who have slow-transit-type primary constipation that is refractory to treatment are also surgical candidates.35 Surgery may be required in some endocrine disorders that cause constipation, such as pheochromocytoma, which requires removal of a tumor. In each case, the involved segment of intestine may be resected or revised.

Biofeedback

Patients with constipation due to pelvic floor dysfunction/disordered defecation may have a less favorable response to fiber therapy than other constipation subtypes.36 Many adult patients with functional defecatory disorders appear to benefit from pelvic floor retraining with biofeedback therapy. The goals of biofeedback are to improve pelvic floor relaxation to facilitate the passage of stool and the procedure is typically performed over 4- to 6-hour-long sessions. Success rates of 65% to 80% have been reported in controlled and uncontrolled studies, and improvement has been sustained for up to 1 year. The value of biofeedback in children with chronic constipation has not been well demonstrated.3

Electrical Stimulation

Sacral nerve stimulation is a minimally invasive technique that has been used for treatment of fecal incontinence and there are some reports of its use in severe refractory chronic constipation.38 However, clinical data supporting the use of electrical stimulation for this purpose are limited and there are currently no recommendations for general practice.

Pharmacologic Therapy

Three general classes of laxatives are discussed in this section: (a) those causing softening of feces in 1 to 3 days; (b) those that result in soft or semifluid stool in 6 to 12 hours; and (c) those causing watery evacuation in 1 to 6 hours (Table 23-9). Other pharmacologic agents available for the treatment of constipation include a calcium channel activator, guanylate cyclase C agonist, and serotonergic agents.

TABLE 23-9 Dosage Recommendations for Laxatives and Cathartics

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Bulk-Forming Agents

Medicinal products, often called “bulk-forming agents,” such as psyllium hydrophilic colloids, methylcellulose, or polycarbophil, have properties similar to those of dietary fiber and may be taken as tablets, powders, or granules.28These agents increase the water content of stool to increase stool bulk and weight and relieve the symptoms of constipation within 3 days of initiating therapy.

Bulk-forming laxatives have few adverse effects. The most common effects include flatulence, abdominal bloating, and distention. Rarely, these agents may lead to bowel obstruction. Patients should also be cautioned to consume sufficient fluid while supplementing with bulk-forming agents to avoid obstruction of the esophagus, stomach, small intestine, and colon.

Emollient Laxatives

Emollient laxatives, including docusate in its various salts, are surfactant agents that work by facilitating mixing of aqueous and fatty materials within the intestinal tract.39 They may increase water and electrolyte secretion in the small and large bowel. Increased stool moisture content should lead to a softer, easier-to-pass stool. These products are generally given orally, although docusate potassium has also been used rectally. With these products, softening of stools occurs within 1 to 3 days of therapy.

Emollient laxatives are ineffective in treating constipation but are used mainly to prevent this condition. They may be helpful in situations in which straining at stool should be avoided, such as after recovery from myocardial infarction, with acute perianal disease, or after rectal surgery. It is unlikely that these agents would be effective in preventing constipation if major causative factors (e.g., heavy opiate use, uncorrected pathology, or inadequate dietary fiber) are not concurrently addressed. The use of mineral oil is generally not recommended due to safety concerns.

Although docusates are generally safe, a few adverse effects have been noted. They may increase the intestinal absorption of agents administered concurrently and alter toxic potential. Reports of increased fecal soiling associated with docusate use in elderly patients may limit their use in this population.39PEG solutions with electrolytes are used as bowl cleansing regimens prior to GI-related procedures.

Hyperosmolar Agents

Lactulose and Sorbitol Lactulose is a nonabsorbable disaccharide that is metabolized by colonic bacteria to low-molecular-weight acids, resulting in an osmotic effect whereby fluid is retained in the colon.39The fluid retained in the colon lowers the pH and increases colonic peristalsis within 2 to 3 days of use. Lactulose increases stool frequency and consistency in patients with chronic constipation (vs. placebo) and may be more effective than fiber alone. In comparison to polyethylene glycol (PEG), lactulose is slightly less effective in increasing stool frequency per week and patients are more likely to need additional products for constipation relief.40 The most common adverse effects include flatulence, nausea, and abdominal discomfort or bloating—although lactulose can be useful in some patients. It may be justified as an alternative for acute constipation or in patients with an inadequate response to increased dietary fiber and bulking agents. In some patients with more complex disease or nonmodifiable risk factors for constipation (such as bedridden, elderly patients with chronic or debilitating illnesses and constipating medications), lactulose may be required on a more regular basis.39 In addition to the adverse abdominal effects associated with lactulose, diarrhea and electrolyte imbalances can occasionally occur. Sorbitol, a monosaccharide, also exerts its effect by osmotic action and has been recommended as a cost-effective alternative to lactulose. It is as effective as lactulose but may cause less nausea and is much less expensive.

Polyethylene Glycol PEG is FDA-approved for treatment of constipation at low doses and is expected to produce a bowel movement in 1 to 3 days.39,40 For this indication, PEG is administered in smaller volumes (10 to 30 or 17 to 34 g per 120 to 240 mL) usually once (or twice) daily. PEG is not absorbed systemically or metabolized by colonic bacteria, and therefore has a lower incidence of adverse effects compared with other osmotic laxatives. Daily use in low dose (17 g) may be safe and effective for up to 6 months.41 PEG is a grade A recommendation from the American College of Gastroenterology for the treatment of chronic constipation and is available as a nonprescription drug.34 The most common adverse effects are GI-related and include nausea, vomiting, flatulence, and abdominal cramping.39 PEG solutions with electrolytes are used as bowl cleansing regimens prior to GI-related procedures.

Magnesium Salts Magnesium salts, including hydroxide, phosphate, and citrate, and sodium phosphate are categorized as saline cathartics.39 These agents are frequently used as bowel preparations prior to diagnostic procedures such as colonoscopy.31 Milk of magnesia (an 8% suspension of magnesium hydroxide), though, may be used occasionally to treat constipation in otherwise healthy adults, but efficacy data are limited. Saline cathartics should not be used on a routine basis. These agents may cause fluid and electrolyte depletion. Also, magnesium or sodium accumulation may occur in patients with renal dysfunction or congestive heart failure. These risks increase with long-term use.

Glycerin Glycerin is usually administered as a suppository and exerts its effect by osmotic action in the rectum. As with most agents given as suppositories, the onset of action is usually less than 30 minutes. Glycerin is considered a safe laxative, although it may occasionally cause rectal irritation. Its use is acceptable on an intermittent basis for constipation or fecal impaction, particularly in children.42

Stimulant Laxatives

Stimulant laxatives such as diphenylmethane (bisacodyl) and anthraquinone (senna and others) derivates primarily affect the colon.39 These agents stimulate the mucosal nerve plexus of the colon and may also affect intestinal fluid secretion by altering fluid and electrolyte transport, and are expected to cause a bowel movement within 8 to 12 hours of administration. Stimulant laxatives may cause severe abdominal cramping and electrolyte imbalances, particularly with chronic use. Compared with placebo, bisacodyl is effective in treatment of constipation43; however, stimulant laxatives are not recommended as first-line treatment. These agents are typically reserved for intermittent use or in patients who fail to respond adequately to bulking and osmotic laxatives. Some patients, though, with severe chronic constipation and nonmodifiable risk factors may use these agents on a more regular basis.28,34

Lubiprostone

Lubiprostone is a chloride channel activator that acts locally in the gut to open chloride channels on the GI luminal epithelium, which, in turn, stimulates chloride-rich fluid secretion into the intestinal lumen. Increased intraluminal fluid secretion helps to soften stool and accelerate GI transit time.27 Lubiprostone (Amitiza) is FDA-approved for chronic idiopathic constipation in adults at a recommended dose of one 24 mg capsule twice daily with food as well as treatment of patients with constipation-predominant irritable bowel syndrome (IBS-C). Clinical trials have shown a significant increase in spontaneous bowel movements in patients treated with lubiprostone versus placebo as well as improvement in straining, stool consistency, and overall constipation severity.44 Lubiprostone appears safe and effective for long-term treatment (up to 48 weeks). For most patients, bowel movements occur within 24 to 48 hours of lubiprostone administration. Common adverse effects include nausea, headache, and diarrhea and may be dose dependent.31 Because of its high cost (especially relative to other available laxative agents) and lack of comparative data with other laxative therapies, lubiprostone is reserved for patients with chronic constipation who fail conventional first-line agents.

Linaclotide

Linaclotide (Linzess) is the newest agent approved for the treatment of constipation and IBS-C.45 It is a synthetic 14-amino-acid peptide that binds to and activates the guanylate cyclase C receptor found on the intestinal epithelium. This increases intestinal fluid secretion and quickens intestinal motility. In two randomized controlled trials involving approximately 1,276 patients, linaclotide 145 and 290 mcg daily was more effective than placebo at increasing spontaneous bowel movements in patients with chronic constipation at 12 weeks.46 Only the 145 mcg dose is approved for treatment of constipation due to the lack of improved efficacy with the higher dosing. Diarrhea was the most commonly reported adverse event in clinical trials, followed by flatulence and abdominal pain. Linaclotide should not be used in patients under the age of 18.45

Opioid Receptor Antagonists

Alvimopan (Entereg) is an oral GI-specific μ-opioid antagonist approved for short-term use in hospitalized patients to accelerate recovery of bowel function after large or small bowel resection.47 It antagonizes the GI (peripheral) effects of opioids without affecting analgesia because it does not cross the blood–brain barrier. Alvimopan is only available through a special use program (ENTEREG access support and education [EASE]), which requires hospitals to register and meet all requirements before the drug can be administered. Additionally, alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days prior to surgery as they may be more sensitive to the drug’s effects. Dosing for alvimopan is as follows: 12 mg capsule administered 30 minutes to 5 hours before surgery and then 12 mg twice daily for up to 7 days or until discharge (maximum of 15 doses).

Methylnaltrexone (Relistor) is μ-receptor antagonist approved for opioid-induced constipation in patients with advanced disease receiving palliative care or when response to laxative therapy has been insufficient.47 This agent does not cross the blood–brain barrier or antagonize analgesia; it acts on peripheral μ-receptors to block unwanted opioid side effects such as constipation. It is administered at a weight-based dose as a subcutaneous injection, usually every other day (no more than once daily), and is contraindicated in patients with known or suspected GI obstruction.

Naltrexone and naloxone are also opioid antagonists. Although they do cross the blood–brain barrier and may potentially reverse CNS effects of opioids (respiratory depression and analgesia), use of naloxone for treatment of opioid-induced constipation may be effective when used in a prolonged-release formulation.47

Other Agents

Prucalopride is a selective 5-hydroxytryptamine-4 (5-HT4) receptor agonist being developed for treatment of chronic constipation and IBS-C.48 It demonstrates proenterokinetic effects (increased colonic motility and transit), specifically in the GI tract. Prucalopride, however, is more selective than the previously available serotonergic agonists cisapride and tegaserod with higher affinity for the 5-HT4 receptor. Receptor selectivity is thought to improve the safety profile of prucalopride over cisapride and tegaserod, which were removed from the market due to concerns for adverse cardiovascular events. In clinical trials, prucalopride significantly increased the number of complete, spontaneous bowel movements in adults with chronic constipation. Constipation symptoms and quality of life were also improved with prucalopride. This agent has been safely tolerated in clinical trials with no adverse cardiovascular effects versus placebo (although data are limited) and is approved for use in Europe. Prucalopride has not yet been approved by the FDA.

Probiotics may be useful in the treatment of constipation. Five randomized controlled trials conducted in children and adults revealed that certain strains of probiotics increased weekly stool frequency.49However, these trials were small (370 patients total) and only slight improvement was realized (one additional stool per week). More studies are needed to strengthen evidence involving probiotics, but these may be an option for patients seeking alternative treatment.

Investigational drugs

Velusetrag and norcisapride are selective 5-HT4 agonists that are currently being developed for chronic constipation.28 Both agents appear to be effective and well tolerated in preliminary studies.

Prevention

For certain groups of patients, such as those recovering from myocardial infarction or rectal surgery, straining at defecation should be avoided. The basis of preventive therapy in these patients should be bulk-forming laxatives. Additionally, the use of docusate is popular, although its effectiveness is debated. In pregnant patients, constipation may result because of alterations in hormones or iron supplementation. As described earlier, bulk-forming laxatives and docusates should be the first line of prevention.

Evaluation of Therapeutic Outcomes

The ultimate goal of treatment for constipation is to prevent further episodes of constipation. Short-term goals include alleviation of acute constipation with relief from symptoms. For patients with chronic constipation, the goals include use of proper diet and decreased reliance on laxatives in addition to relief of symptoms for the patient so that quality of life is not diminished. Effective treatment of constipation requires the patient to become more knowledgeable about the causes of constipation, proper diet, and appropriate use of laxatives.

IRRITABLE BOWEL SYNDROME

IBS is a GI syndrome characterized by chronic abdominal pain and altered bowel habits in the absence of any organic cause. It is the most commonly diagnosed GI condition.

Epidemiology

The prevalence of IBS is approximately 10% to 15% based on North American and European population-based studies; however, there is a wide variation in prevalence by individual country.5053 IBS affects men and women, young patients, and the elderly with an overall 2:1 female predominance in North America.52 However, younger patients and women are more likely to be diagnosed with IBS. Although only 15% of those affected actually seek medical attention, IBS is the cause of between 25% and 50% of all referrals to gastroenterologists.50

Pathophysiology

Although the exact pathophysiologic abnormalities with IBS are still being actively investigated, IBS likely results from altered somatovisceral and motor dysfunction of the intestine from a variety of causes. Abnormal CNS processing of afferent signals may lead to visceral hypersensitivity, with the specific nerve pathway affected determining the exact symptomatology expressed. This visceral hypersensitivity is a neuroenteric phenomenon that is independent of motility and psychological disturbances.54 Factors known to contribute to these alterations include genetics, motility factors, inflammation, colonic infections, mechanical irritation to local nerves, stress, and other psychological factors.

Serotonin-Type Receptors

The enteric nervous system contains a significant percentage of the body’s 5-HT.55 Two types of 5-HT exist within the gut: serotonin type 3 (HT3) and serotonin type 4 (HT4), which are responsible for secretion, sensitization, and motility. There is an increase in the postprandial levels of 5-HT in those who suffer from diarrhea-predominant IBS when compared with nonsufferers.55 Therefore, stimulation and antagonism of these 5-HT receptors have become a focused area for research on new drug therapies for both diarrhea-and constipation-predominant diseases.

Clinical Presentation

Images IBS presents as either diarrhea- or constipation-predominant disease and can be defined as lower abdominal pain, disturbed defecation (constipation, diarrhea, or an alternating pattern of both), and bloating in the absence of structural or biochemical factors that might explain these symptoms (Table 23-10). Because IBS can consist of a variable number of signs and symptoms, two diagnostic criteria “checklists” are commonly used to aid in the workup of a patient suspected of having IBS. The Manning criteria were first proposed in 1978, whereas the Rome criteria were initially proposed in 1999 and revised as recently as 2006 by an international working group in an effort to help standardize the diagnostic criteria used in clinical research protocols. Table 23-11 shows the symptom criteria for both of the Manning56 and Rome III33 symptom-based criteria.

TABLE 23-10 Clinical Presentation of Irritable Bowel Syndrome

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TABLE 23-11 Symptom-Based Criteria for Irritable Bowel Syndrome

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Additional diagnostic steps that can be taken include sigmoidoscopy or colonoscopy, examination of the stool for occult blood and ova and parasites, complete blood cell count, erythrocyte sedimentation rate, and serum electrolytes. In some cases, radiographic imaging studies, such as computed tomography scans or barium swallows or enemas, may also be necessary if the findings of the foregoing assessment are not typical for IBS.50

TREATMENT

General Approach to Treatment

The treatment approach to IBS is based on the predominant symptoms and their severity (Fig. 23-3). Milder, less frequent episodes can be managed with dietary restrictions and a higher-fiber diet, with addition of bulk-forming laxatives, if necessary. More persistent disease may require as-needed uses of various antispasmodic or antidiarrheal agents such as loperamide. Lastly, the most severe forms of this disease may call for pharmacologic agents directed specifically at the underlying neurohormonal imbalance, such as the 5-HT4 agonists (e.g., tegaserod), or the 5-HT3 receptor antagonists (e.g., alosetron).

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FIGURE 23-3 A general stepwise approach to the management of both constipation- and diarrhea-predominant irritable bowel syndrome. aConsider manufacturer-sponsored patient access program.

Alosetron, a 5-HT3 receptor antagonist, was withdrawn from the U.S. market in 2000 as a result of serious adverse effects, including severe constipation and ischemic colitis that did not appear in the initial clinical trials. It was reintroduced in 2002 and is now limited to an FDA-approved restricted-use program in lower initial doses, and requires extensive postmarketing surveillance. Results of these trials are necessary to definitively determine alosetron’s true safety profile, especially with regard to its association with or causation of fatal ischemic colitis.

Constipation-Predominant Disease

In the constipation-predominant patient, dietary fiber may be beneficial. Patients should be instructed to begin with one tablespoonful of fiber with one meal daily and gradually increase the dose to include fiber with two and three meals a day until the desired outcome is achieved. End points that the patient should aim for include bulkier and more easily passed stools. For patients unable to tolerate dietary bran, bulking agents such as psyllium may be substituted.57 Laxative use is not encouraged in these patients, and it should only be used in the smallest dose for the least amount of time in cases of severe constipation.

The 5-HT4 partial agonist tegaserod was the first therapy approved by the FDA specifically for short-term, intermittent treatment of IBS-C.58 tegaserod was suspended from marketing in early 2007 at the request of the FDA due to an analysis of clinical trial data showing a small, yet significant, increase in ischemia events (MI, cerebrovascular accident [CVA], and unstable angina) in patients with preexisting cardiovascular disease and/or cardiovascular risk factors. In July 2007, the drug’s manufacturer, Novartis, began a tegaserod (Zelnorm) restricted-access program for patients in the United States. Tegaserod is a 5-HT derivative that activates 5-HT4 receptors on the neurons in the GI tract, increasing GI motility and decreasing visceral sensations. It is approved as 2 or 6 mg doses given twice daily 30 minutes prior to a meal with water for up to 12 weeks.59 Stimulation of the 5-HT4 receptors by tegaserod increases gastric secretions and promotes motility, with improvement in symptoms generally occurring within the first week of therapy. Currently this therapy is only approved for use in women; efficacy and safety in men have not been established because of inadequate numbers of men enrolled in clinical trials to date.60Diarrhea was the most common adverse effect, resulting in drug discontinuation in 1.6% of study subjects.

Diarrhea-Predominant Disease

Images For patients in whom diarrhea is the primary complaint, avoidance of certain food products may be necessary. Caffeine, alcohol, and artificial sweeteners (sorbitol, fructose, and mannitol) are known to irritate the gut and produce a laxative effect. Lactose intolerance should be considered in certain patients; however, the prevalence of this condition may be exaggerated.

Herbal medicines or teas often contain senna, which may produce diarrhea. In patients with disease persistence following dietary modification, loperamide may be used for episodic management of urgent diarrhea, or in situations in which the patient wishes to avoid the possibility of an acute onset of symptoms.59 Loperamide decreases intestinal transit, enhances water and electrolyte absorption, and strengthens rectal sphincter tone. Some patients may require continuous therapy, and careful dosage titration can usually be undertaken to prevent the development of constipation.

Diarrhea-predominant IBS caused by excessive stimulation of the 5-HT3 receptor can be relieved by the drug alosetron. Alosetron was the first effective treatment for diarrhea-predominant IBS.55 However, in November 2000 it was voluntarily withdrawn from the market because of severe GI adverse effects, including 113 reported cases of serious constipation and 8 cases of possible ischemic colitis and death. This decision was met with a great public outcry, as many who had suffered for years had experienced relief for the first time. Because this drug was highly effective in many patients, the FDA approved restricted use of alosetron in June 2002. Alosetron is now available via an FDA-approved restricted-use program in conjunction with GlaxoSmithKline as detailed at http://www.lotronex.com. It is now indicated, in lower initial doses of 0.5 mg twice daily, for women with diarrhea-predominant symptoms of longer than 6 months’ duration that are not relieved by conventional therapy. Healthcare providers must use extreme caution in therapy with this drug and must follow strict FDA-mandated guidelines.

Probiotics (see Diarrhea above) such as Lactobacillus and Bifidobacterium reduced IBS symptoms in several investigative trials.17 Another 5-HT3 antagonist, cilansetron, has demonstrated efficacy similar to that of alosetron in phase II trials and enrolled enough male patients to show benefit in males as well.55

Use of Antidepressants in Irritable Bowel Syndrome

Tricyclic antidepressants have shown some benefit in treatment of diarrhea-predominant IBS associated with moderate to severe abdominal pain, by modulating perception of visceral pain, altering GI transit time, and treating underlying comorbidities.61,62 Selective 5-HT reuptake inhibitors are less well studied, with only one report with paroxetine showing some improvement in stool passage and “well-being” but no decrease in abdominal pain.6365

Figure 23-3 shows a general stepwise approach to the management of both constipation and diarrhea-predominant IBS.

Pain in Irritable Bowel Syndrome

Images Some patients with IBS suffer significant pain associated with their disease. Data supporting the use of antispasmodic agents in these patients are conflicting.50 A trial of low-dose antidepressant therapy is indicated, especially if pain is associated with eating. Both tricyclic antidepressants and 5-HT reuptake inhibitors produce analgesia and may relieve depressive symptoms if present. Preprandial doses of drugs containing anticholinergic properties may suppress pain (and/or diarrhea) associated with an overactive postprandial gastrocolonic response. Tricyclic antidepressants should be avoided in patients with pain and constipation. In addition, psychotherapy, including cognitive behavioral therapy, relaxation therapy, and hypnotherapy, has been shown to decrease IBS symptoms.66

Evaluation of Therapeutic Outcomes

IBS is usually classified as constipation-predominant, diarrhea-predominant, or IBS with abdominal pain and bloating. Therapeutic goals in IBS should focus on the patient’s primary complaint. Dietary and drug therapy goals should focus on end-organ treatment to relieve abdominal pain (antispasmodic drugs) or disturbed bowel habits (antidiarrheals and bulk-forming agents). Additionally, severe symptoms from CNS dysregulation should be treated with antidepressants, psychotherapy, relaxation/stress management, cognitive behavior treatment, and/or hypnosis aimed at specific affective disorders.50 Lastly, the 5-HT receptor agonists and antagonists can be used in carefully selected patients whose symptoms are not adequately controlled with other agents. The AGA recommends that patients with severe IBS consider psychological treatments such as psychotherapy, relaxation/stress management, and/or cognitive behavior treatment.

ABBREVIATIONS

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REFERENCES

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