Comorbidity of GI Motility Disorders: Clinical Implications for Patients and Pharmacists

Brought to you through an educational grant fromNovartis.

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

• Define gastrointestinal (GI) motility disorders as a group, and review common symptoms of irritable bowel syndrome (IBS), chronic constipation, gastroesophageal reflux disease (GERD), and functional dyspepsia.
• Discuss the prevalence and socioeconomic impact of GI motility disorders.
• List examples of comorbidity and symptom overlap between IBS, chronic constipation, functional dyspepsia, and GERD, and discuss the tendency of symptom patterns to evolve over time.
• Summarize treatment strategies for each disorder (listed above), and discuss clinical consequences of polypharmacy.
• Recite 3 examples of ways pharmacists can help patients with comorbid GI motility disorders manage their conditions safely and effectively.

See Exam on Page 93

The gastrointestinal (GI) tract refers to the long food-processing tube that consists of the mouth, pharynx, esophagus, stomach, small intestine, large intestine, rectum, and anus. The term GI motility refers to movement anywhere along this tract. GI motility disorders can develop when nerves or muscles in any portion of the digestive tract fail to function properly, resulting in decreased, increased, or disorganized movement, as well as changes in visceral sensation and perception. Resultant symptoms can manifest in many forms, including heartburn, bloating, nausea, vomiting, diarrhea, and constipation.^1,2

GI motility disorders such as irritable bowel syndrome (IBS), chronic constipation, gastroesophageal reflux disease (GERD), and functional dyspepsia are highly prevalent conditions. Symptoms associated with these disorders often are bothersome and prevent those affected from leading full and productive lives. These symptoms hamper the ability to participate in social activities (eg, sports, shopping, traveling, dining out with friends) and may prevent people from maintaining personal relationships.^3-22

Additionally, as a result of direct costs (eg, outpatient and inpatient visits, diagnostic procedures, medications) and indirect costs (eg, decreased work productivity, absenteeism from work or school), these disorders frequently are associated with a heavy economic burden on society.^8-22 For example, annual direct costs (excluding Rx and OTC meds) of IBS are estimated to be as high as $10 billion⁸ and indirect costs as high as $20 billion.⁹ In the Truth in IBS Survey (n = 318 adults with IBS), participants reported missing >2x as many days from work in the 12 months before the survey as did persons without IBS (6.4 vs 3.0 days, respectively).³

Symptoms of GI motility disorders often overlap with one another, and comorbidity among these disorders is high (Figure 1).²³ For instance, 22% to 50% of patients with functional dyspepsia also have GERD, and 29% of patients with GERD have chronic constipation.^24,25 Results of a systematic review of published data (1996-2002) demonstrate that 23% to 87% of patients with IBS also have dyspepsia, 13% to 87% of patients with dyspepsia also have IBS, 46.5% of patients with IBS also have GERD, and 47% of patients with GERD also have IBS.²³

In a recently published population-based study (n = 643), overall prevalence rates were as follows: IBS, 12%; dyspepsia, 14%; GERD, 20%; diarrhea, 21%; and constipation, 17%. Analysis of coprevalence of symptom complexes revealed that 4% to 9% of the population exhibited symptom complexes consistent with at least 2 of these conditions and that 1% to 4% of the population exhibited symptoms consistent with at least 3 of these conditions.²⁵ Furthermore, in a given patient, symptom patterns consistent with one disorder may evolve over time to be consistent with a different GI motility disorder.²⁶

Clinical implications of the high prevalence of symptom overlap and comorbidity among GI motility disorders with regard to pharmacy practice are numerous. The high potential for polypharmacy is among the most important. Treatment regimens for these multisymptom conditions often include OTC, alternative, or prescription medications (Table 1),^{5,16,19,32-52} potentially resulting in therapy duplication, drug interactions, or adverse effects. Furthermore, treatments targeting a particular symptom may mimic or exacerbate other symptoms of that disorder or those of comorbid disorders. Because of efficacy limitations and problems with adverse events, many patients are dissatisfied with traditional treatment options. Pharmacists can play an important role in assisting patients in the safe and effective management of comorbid GI motility disorders.

Symptomatology, Pathophysiology, and Treatment Recommendations

Irritable Bowel Syndrome

IBS has no serologic, biochemical, or physiologic markers or any associated structural abnormalities; thus, it is diagnosed based on symptoms and patient history.²⁷ IBS is characterized by abdominal discomfort or pain associated with altered bowel habits (constipation, diarrhea, or alternation between the two).²⁸ Although the pathophysiology of IBS has not been fully described, increasing evidence implicates involvement of the serotonergic pathway.^29,30 Although many neurotransmitters are involved in regulating GI motility, secretion, and sensation, serotonin is a major player in all 3 of these processes. Serotonin has an important role in communication, not only within the GI tract (enteric nervous system [ENS]), but also between the ENS and the central nervous system (CNS). It is often overlooked that 95% of the body's serotonin is made and stored in the ENS, where it functions as a critical component of normal GI tract function and serves as the main initiator of peristalsis.²⁹

Modulation of serotonin activity, by blocking or activating certain serotonin receptors, has been shown to alter GI motility, secretion, and visceral sensation and to relieve symptoms in patients with IBS. Recent data suggest that there are alterations in serotonin synthesis and signaling in patients with IBS.³¹ Modulation of 5-hydroxytryptamine type 3 (5-HT³) receptors using 5-HT₃ receptor antagonists such as alosetron (Lotronex; GlaxoSmithKline, Research Triangle Park, NC) decreases GI motility and visceral sensation. It also provides global relief of IBS symptoms (eg, abdominal pain/discomfort, diarrhea, and urgency) in patients with IBS with diarrhea. In contrast, modulation of 5-HT₄ receptors using 5-HT⁴ receptor agonists such as tegaserod (Zelnorm; Novartis, Basel, Switzerland) increases GI motility and intestinal secretion and reduces visceral sensation. This agent provides global relief of IBS symptoms (eg, abdominal pain/discomfort, bloating, and constipation) in patients with IBS with constipation.³²

For patients with IBS, the goals of therapy are to provide global and individual symptom relief and to improve overall well-being. Treating altered bowel habits without addressing the other symptoms is considered suboptimal.¹⁴ Because of the multisymptom nature of this condition and the oftentimes insufficient efficacy and associated adverse effects of traditional agents, multiple treatments (including OTC, alternative, and prescription medications) often are used. Treatment options for IBS include diet and lifestyle modification, bulking agents, laxatives, antidiarrheals, antispasmodics/anticholinergics, antidepressants, tegaserod, and alosetron. In 2002, the American College of Gastroenterology (ACG) Functional Gastrointestinal Disorders Task Force published an evidence-based position statement on the management of IBS and a systematic review of medications used for the treatment of IBS. Parameters for this evidence-based approach are found in Table 2.²⁸

Diet and lifestyle modifications include increasing dietary fiber intake, increasing water intake, exercising regularly, and modifying the intake of foods that exacerbate symptoms, such as beans and other gas-producing foods, fatty foods, alcohol, caffeine, lactose (for those with intolerance), and excess fiber (for those with diarrhea).^53,54 Bulking agents include wheat bran, corn fiber, calcium polycarbophil, ispaghula husk, and psyllium. These agents accelerate intestinal transit and may relieve constipation; however, they also may increase gas, bloating, and abdominal discomfort.³² Based on published evidence, the ACG task force concluded that commonly available bulking agents were no more effective than placebo at relieving global IBS symptoms (grade B recommendation/intermediate-quality evidence).³² If bulking agents do not relieve the constipation, an osmotic laxative such as lactulose or milk of magnesia often is effective, although it can cause abdominal cramping.⁵⁵ In general, there are no data to support the use of these agents in patients with IBS.

Antidiarrheal agents slow intestinal transit time and may provide relief to the IBS patient with diarrhea. Loperamide is the only antidiarrheal agent that has been evaluated in IBS patients. It was found to be effective at relieving diarrhea, but the ACG task force also considered it no more effective than placebo at providing global symptom improvement (grade B recommendation/ intermediate-quality evidence).³²

Antispasmodics and anticholinergics function to decrease bowel motility, abdominal pain, and bloating. Adverse effects associated with these drugs include visual disturbances, urinary retention, dry mouth, and constipation. Agents with data supporting their use in IBS patients are unavailable in the United States.³²

Some antidepressants, mostly tricyclic antidepressants (TCAs; eg, desipramine), have been effective at reducing abdominal pain in the IBS patient.³² Because these agents may cause constipation, however, they should be used with caution in IBS patients with constipation.³² Although the ACG task force concluded that these agents improve abdominal pain, they noted that the drugs are no more effective than placebo at providing global IBS symptom relief (grade B recommendation/intermediate-quality evidence). Data on the use of selective serotonin reuptake inhibitors in the treatment of IBS are limited, but evidence shows that they are effective at decreasing abdominal pain.³²

As mentioned, the serotonergic agents tegaserod and alosetron are the only treatments that target the multiple symptoms of IBS. Tegaserod is the only agent indicated by the FDA for the treatment of women with IBS with constipation, and alosetron is the only FDA-approved treatment for women with IBS with diarrhea. Because of their high-quality clinical trial evidence, these agents were found to be more effective than placebo at relieving IBS symptoms, and they received grade A recommendations (high-quality evidence) from the ACG task force.³²

Chronic Constipation

Contrary to popular belief, a formal definition of constipation does not currently exist. Physicians typically describe this condition in an objective manner (in terms of bowel frequency), whereas patients often describe more qualitative aspects, including hard or small stools, straining, incomplete evacuation, and abdominal pain/bloating.^56,57 Also, currently no standard definition exists for the term chronic constipation. In general practice, occasional constipation refers to symptoms that have lasted for 3 months or less and that have responded to self-treatment measures, and chronic constipation refers to symptoms that have lasted for 3 months or longer and for which selftreatment approaches have been ineffective at relieving symptoms.

Constipation is typically categorized as secondary (induced by a specific condition or medication) or primary (idiopathic, occurring from an unknown cause).³³ Examples of secondary causes of constipation include metabolic and endocrine disorders (eg, diabetes mellitus, hypercalcemia); neurologic disorders (eg, Parkinson's disease, cerebrovascular disease); and systemic disorders (eg, scleroderma, amyloidosis, polymyositis). Numerous medications also are associated with constipation, including TCAs, antispasmodics, and calcium-and aluminum-containing antacids.^58,59

Primary constipation is typically subcategorized as normal-transit (stool transit through the colon occurs at a normal rate, but patients report feeling constipated) or slow-transit (transit through the colon is delayed) and as defecatory or rectal evacuation disorders (also known as anismus, pelvic floor dyssynergia, dyssynergic or obstructive defecation, or outlet obstruction). Chronic constipation may be the result of 1 mechanism or a combination of these mechanisms.³³

The underlying causes of primary constipation have not been firmly elucidated. Slow-transit constipation may occur as a result of a disturbance in the ENS or of smooth muscle dysfunction.⁶⁰ As with IBS, abnormalities in serotonin synthesis or signaling also may play a role; such abnormalities have been demonstrated in patients with slow-transit constipation.^61,62 Disorders of defecatory function, characterized by difficulty or inability to expel stool from the anorectum, may occur as a result of anatomic abnormalities such as excessive perineal descent or rectal prolapse, or they can occur because of poor coordination between the pelvic floor muscles and the external or internal anal sphincters during defecation.³³

Goals of therapy in chronic constipation are to restore regularity, improve normal bowel function, and provide relief of key symptoms, including straining, hard/lumpy stools, feelings of incomplete evacuation, infrequent bowel movements, and bloating/fullness.⁶³ In general, for patients in whom symptoms are not severe, nonpharmacologic measures (lifestyle modifications) are tried first, such as increasing consumption of dietary fiber, maintaining adequate fluid intake, and exercising. In patients with chronic constipation, however, the usefulness of these measures from an evidence-based perspective has not been proven.^64,65

For patients in whom lifestyle measures alone fail to provide adequate symptom relief, common treatment options include bulking agents, laxatives (bulk, osmotic, stimulant), cholinergic agents, and promotility agents.³³

Results from 2 recently published evidence-based evaluations of treatment options for patients with chronic constipation^16,65 reveal the lack of high-quality data demonstrating efficacy of many commonly used agents for patients with chronic constipation. The review by Ramkumar and Rao⁶⁵ was based on the parameters shown in Table 3.⁶⁵

Based on these parameters, grade A recommendations (good-quality evidence) were given for polyethylene glycol (PEG) and tegaserod; grade B recommendations (fair-quality evidence) for psyllium and lactulose; and grade C recommendations (poor-quality evidence) for methylcellulose, bran, senna, bisacodyl, docusate, magnesium hydroxide, and calcium polycarbophil. Pharmacists should note, however, that all formulations of PEG were included in this review (eg, PMF-100, PEG 3350, PEG/electrolyte solutions, and high-molecular-weight PEG [PEG 4000]), but that only PEG 3350 (MiraLax; Braintree Laboratories, Braintree, Mass) has received FDA approval (for the treatment of patients with occasional constipation). Quality scores for the 2 trials that used PEG 3350 were level 3 (poor).⁶⁵

Similar results were demonstrated in the systematic review conducted by the ACG Task Force on the Management of Chronic Constipation in North America.¹⁶ The parameters for this review were the same as those used in the systematic review of IBS therapies (Table 2). Based on published data, PEG, lactulose, and tegaserod all received grade A recommendations (high-quality evidence), whereas grade B recommendations (intermediate-quality evidence) were assigned to bran, methylcellulose, psyllium, calcium polycarbophil, milk of magnesia, and stool softeners.¹⁶ As with the systematic review conducted by Ramkumar and Rao,⁶⁵ all formulations of PEG were included in this review.

Gastroesophageal Reflux Disease/ Nonerosive Reflux Disease

GERD is a condition in which symptoms or mucosal damage (confirmed by endoscopy and esophageal pH monitoring) occur as a result of abnormal reflux of gastric contents into the esophagus.³⁸ This condition is characterized by symptoms of heartburn (often described as a burning sensation behind the breastbone that projects toward the throat) or acid regurgitation (sour taste in the mouth resulting from reflux of gastric contents) that often occur after meals.^66,67 Examples of less typical symptoms of GERD include early satiety, bloating, nausea, chronic cough, noncardiac chest pain, and insomnia.^5,19,68

The exact pathophysiology of GERD remains unknown. Potential factors that allow the reflux of gastric contents into the esophagus include an incompetent lower esophageal sphincter; the presence of a hiatal hernia (which disrupts the gastroesophageal junction); poor esophageal clearance; and delayed gastric emptying.¹⁹ The end result of gastric contents not being cleared promptly is esophageal exposure to gastric acids and, ultimately, esophageal mucosal damage. Interestingly, most patients (up to 70%) with classic GERD symptoms have no evidence of damage to the esophageal mucosa.⁶⁶ This patient subgroup often is considered to have nonerosive reflux disease (NERD). For these patients, factors other than acid may cause symptoms, such as motility dysfunction and visceral hypersensitivity.^66,68,70

Primary treatment goals in patients with GERD include achievement of symptom relief, prevention of symptom relapse, healing of erosive esophagitis, and prevention of complications of esophagitis (eg, Barrett's esophagus, a condition that can progress to esophageal adenocarcinoma).^5,38,71 In the absence of GERD-related complications, a trial of lifestyle modifications (eg, elevating the head of the bed, decreasing fat intake and meal size, quitting smoking, losing weight) generally is among the first approaches implemented.

In general, the mainstay of therapy for patients with GERD is acid suppression with agents such as OTC acid suppressants and antacids, histamine²- receptor antagonists (H²RAs), and proton pump inhibitors (PPIs). Promotility agents also may relieve symptoms in some patients.^5,38

Updated guidelines on the diagnosis and treatment of patients with GERD were recently published by the ACG.³⁸ Within these guidelines, treatment options were rated by levels of evidence, as shown in Table 4.³⁸

According to these guidelines, lifestyle modifications (level 4 evidence) may help many GERD patients; however, this option alone will not provide complete symptom control in most patients. OTC antacids and antirefluxants (alginic acid; level 4 evidence) play a prominent role in the treatment of milder forms of heartburn and regurgitation. H²RAs are effective at reducing gastric acid, especially after a meal and in patients with less severe symptoms (level 4 evidence), whereas PPIs (level 1 evidence) are the drug class that provides the most effective and rapid symptom relief and that heals esophagitis in the highest percentage of patients.³⁸ The usefulness of this therapeutic class is less clear in patients with NERD, however, because factors other than acid may play a prominent role.^68-70 In these patients, promotility agents (eg, metoclopramide, bethanechol, tegaserod) that improve esophageal peristalsis and enhance gastric emptying may represent an important adjunct to acid-suppression therapy (level 2 evidence).³⁸

The CNS-associated adverse effects of metoclopramide and bethanechol (eg, drowsiness, irritability, extrapyramidal effects) limit their regular use.^38,45 Tegaserod, which has promotility and antinociceptive properties, was recently shown to decrease the frequency of postprandial esophageal acid reflux episodes in GERD patients³⁹ and to alter the esophageal pain threshold and improve upper GI symptoms in patients with functional heartburn.^47,48

Functional Dyspepsia

Functional dyspepsia refers to the presence of pain or discomfort in the upper abdominal area in the absence of an identifiable cause (ruled out after extensive diagnostic evaluation).^20,72 Symptom manifestations of this condition (which often accompany food ingestion) can include epigastric pain, epigastric burning, bloating, abdominal pain/discomfort, early satiety, fullness, belching, nausea, and vomiting.⁷²

The underlying pathophysiologic cause of functional dyspepsia remains unknown. Examples of potential etiologic factors include delayed gastric emptying (which affects up to 50% of patients); abnormalities in gastric motility; reduced accommodation to a meal; hypersensitivity to gastric distension; Helicobacter pylori infection (the role of which is unclear); and abnormal gastric electrical rhythm.^23,40,73 Altered serotonin signaling also may play a role.²⁶ Several of these underlying etiologic factors (eg, abnormalities in gastric motility, visceral sensation, serotonin signaling) overlap with those implicated in IBS. These pathophysiologic corollaries and the high prevalence of symptom overlap have led some authors to question the appropriateness of separating these disorders into 2 distinct entities.²⁶

The goals of therapy for functional dyspepsia include the normalization of gastric emptying and motility with promotility agents; acid suppression (particularly in patients with reflux-like dyspepsia); and, in some patients, the eradication of H pylori.⁴¹ Antidepressants often are prescribed to treat visceral hypersensitivity and CNS-associated dysfunction.⁴¹ Overall, available treatments used to treat patients with functional dyspepsia are considered only marginally effective at providing symptom relief.^40,74

Although antisecretory agents commonly are used in the management of patients with functional dyspepsia, few data support their overall efficacy. Symptom relief with omeprazole has been demonstrated in patients with reflux-like dyspepsia but has not been shown consistently in those with dysmotility-like dyspepsia.^40,41 H²RAs relieve pain associated with functional dyspepsia but not the overall symptoms,⁴⁰ and proven benefits of antacids in patients with functional dyspepsia are scarce.⁴¹ Because of their neuromodulatory and analgesic properties, lowdose antidepressants (eg, amitriptyline) may be beneficial in this patient population. Studies with selective serotonin reuptake inhibitors are ongoing.^40,41 In addition, numerous promotility agents?including metoclopramide, domperidone, and tegaserod?have been used successfully to treat dyspepsia.^40,75

Results of a recently published Cochrane review confirm the lack of high-quality, evidence-based data to support the use of many commonly used medications for the treatment of patients with functional dyspepsia.⁷⁶ Overall, the quality of most clinical trials was poor (eg, in terms of duration, length of follow-up, exclusion of patients with reflux disease), and results demonstrated a high placebo-response rate (56%; range, 5%-90%). A positive response was demonstrated by antisecretory agents (PPIs, H²RAs), prokinetics (metoclopramide, domperidone, cisapride), and mucosal protectants (misoprostol, bismuth, sucralfate), but not by antacids. The investigators concluded that, in a small proportion of patients with functional dyspepsia, antisecretory therapy is effective.

Evidence was strongest for PPIs (based on lack of publication bias and quality of clinical trials). Although a positive response was demonstrated by prokinetics, given the potential publication bias, clinical implications remain unclear.⁷⁶

Conclusion

For many patients, GI motility disorders are highly bothersome conditions for which pharmacologic treatment often is required. Because of the high prevalence of symptom overlap and comorbidity, the likelihood of polypharmacy among patients with these disorders is high. Through proactive patient counseling regarding potential adverse effects and drug interactions, pharmacists can play an important role in assisting patients with safe and effective management of their comorbid GI motility disorders.

One important point to communicate to patients is the need to inform their primary care physicians if they are under treatment by any other health care professional(s) for related GI disorders. Given the dearth of effective treatment options for many GI motility disorders, patients may become frustrated at the slow progress of their conditions or the adverse effects they are experiencing from various agents. Pharmacists have the invaluable opportunity to counsel patients on available treatments (including the similarities in mechanism of action of numerous pharmacologic agents and the associated potential risks of concomitant use).

Whenever possible, pharmacists also should warn patients of potential adverse effects, particularly those that may mimic or exacerbate their current symptoms. For instance, the use of bulking agents may relieve constipation but may cause or exacerbate gas, bloating, and abdominal discomfort. Pharmacists also can serve as the vital link between patients and their health care providers, counseling patients about the dangers of potential therapeutic overlap and informing physicians about issues patients may be facing with their medications.

Danial E. Baker, PharmD, FASHP, FASCP: Associate Dean for Clinical Programs, Professor of Pharmacotherapy, Washington State University

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@ascendmedia.com.

(Based on the article starting on page 85) Choose the 1 most correct answer.

1. Gastrointestinal (GI) motility disorders affect which part of the GI tract?

• Upper GI tract
• Stomach and intestines
• Colon and rectum

Any part of the GI tract

2. The primary abnormality in GI motility disorders is:

• Alteration of normal gut flora.
• Altered GI motility and sensation.
• Altered intestinal absorption.

Up-regulation of histamine² receptors in the stomach.

3. Symptoms of GI motility disorders include all of the following except:

• Heartburn.
• Diarrhea and constipation.
• Halitosis.

Nausea and vomiting.

4. Which of the following agents received a grade A recommendation by the American College of Gastroenterology task force for efficacy in providing global relief of the multiple symptoms of irritable bowel syndrome (IBS)?

• Anticholinergics/antispasmodics
• Antidepressants
• Serotonergic agents

Both A and C

5. All of the following factors may contribute to the development of GERD except:

• Enhanced gastric emptying.
• Incompetent lower esophageal sphincter.
• Poor esophageal clearance.

Presence of a hiatal hernia.

6. Which of the following is true about GI motility disorders?

• There is a high degree of symptom overlap among disorders.
• There is a high potential for polypharmacy among patients.
• There is a high degree of comorbidity in these disorders.

All of the above

7. Which of the following treatment options target single symptoms of IBS (with constipation or diarrhea)?

• Proton pump inhibitors
• Laxatives and antidiarrheals
• Serotonergic agents (tegaserod and alosetron)

Both B and C

8. Antidepressants may relieve which of the following symptoms associated with select GI motility disorders?

• Constipation
• Bloating
• Abdominal pain

Diarrhea

9. Bulking agents have a place in therapy for which of the following disorders?

• IBS and GERD
• IBS only
• Chronic constipation only

IBS and chronic constipation

10. Proton pump inhibitors are used to relieve symptoms of which of the following conditions?

• GERD and functional dyspepsia
• GERD and IBS
• GERD, functional dyspepsia, and IBS

GERD only

11. Which of the following statements is true?

• Laxatives can help to relieve the abdominal pain associated with IBS and chronic constipation.
• Tricyclic antidepressants can relieve the constipation associated with IBS and chronic constipation.
• Bulking agents can relieve abdominal pain and constipation associated with IBS and chronic constipation.
• Bulking agents can relieve the gas and bloating associated with IBS and chronic constipation.