Therapy for Irritable Bowel Syndrome
http://www.100md.com
《新英格兰医药杂志》
To the Editor: I commend Mertz for his comprehensive review of irritable bowel syndrome (Nov. 27 issue).1 However, some comments are warranted. Mertz refers to tegaserod as "a drug similar to the prokinetic agent cisapride," but in fact it is structurally and pharmacologically distinct from cisapride (Table 1). Tegaserod represents a new class of drug (aminoguanidine indoles) and is a partial 5-hydroxytryptamine4 (5-HT4)–receptor agonist. Cisapride is a substituted benzamide that acts as a 5-HT4–receptor agonist and a 5-HT3–receptor antagonist. Tegaserod does not affect cardiac conduction.2
Table 1. Structural and Pharmacologic Characteristics of Tegaserod and Cisapride.
Stratifying treatment recommendations can be problematic. Studies indicate that patients' distress, when compared with the severity of individual symptoms, is important.4 The overall discomfort level, not the severity of gastrointestinal symptoms, should guide therapy. Tegaserod is approved by the Food and Drug Administration for women with irritable bowel syndrome and constipation, with no restrictions related to the severity of symptoms. The only therapy for irritable bowel syndrome that has restrictions is alosetron (used for severe irritable bowel syndrome with diarrhea), because of its safety profile and association with ischemic colitis.
Mertz correctly portrays antidepressants as efficacious for irritable bowel syndrome. However, this use of antidepressants is evolving; recent studies suggest that the side-effect profile of antidepressants affects patients' acceptance of them in important ways.5
Kevin W. Olden, M.D.
Mayo Clinic Scottsdale
Scottsdale, AZ 85259
References
Mertz HR. Irritable bowel syndrome. N Engl J Med 2003;349:2136-2146.
Morganroth J, Ruegg PC, Dunger-Baldauf C, Appel-Dingemanse S, Bliesath H, Lefkowitz M. Tegaserod, a 5-hydroxytryptamine type 4 receptor partial agonist, is devoid of electrocardiographic effects. Am J Gastroenterol 2002;97:2321-2327.
Kamm MA. The complexity of drug development for irritable bowel syndrome. Aliment Pharmacol Ther 2002;16:343-351.
Hahn BA, Kirchdoerfer LJ, Fullerton S, Mayer E. Patient-perceived severity of irritable bowel syndrome in relation to symptoms, health resource utilization and quality of life. Aliment Pharmacol Ther 1997;11:553-559.
Drossman DA, Toner BB, Whitehead WE, et al. Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology 2003;125:19-31.
To the Editor: In his review of irritable bowel syndrome, Mertz recommends fiber for irritable bowel syndrome with constipation, followed by osmotic laxatives and antispasmodic agents. He also recommends antispasmodic agents for irritable bowel syndrome in which pain predominates. This approach reflects experience-based management of the syndrome, but there may not be adequate evidence to support these recommendations.
No randomized, controlled trials have evaluated the efficacy of osmotic laxatives in patients with irritable bowel syndrome. Mertz notes that "data are lacking" to support the efficacy of fiber in these patients. These assertions are supported by a recent systematic review of the methodologic quality and results of trials of therapy for irritable bowel syndrome.1 The antispasmodic agents available in the United States (dicyclomine and hyoscyamine) have not been found to be beneficial in appropriately designed randomized, controlled trials.1 Although benefit with other antispasmodic agents has been found in meta-analyses,2,3 these trials, as Mertz states, "lacked appropriate blinding, had small numbers of patients, were of short duration, and used unclear criteria to define a clinical response." Given these methodologic limitations, it is inappropriate to report numbers needed to treat and odds ratios for therapies for irritable bowel syndrome in a single table (i.e., Mertz's Table 2).
Philip S. Schoenfeld, M.D.
University of Michigan School of Medicine
Ann Arbor, MI 48105
Editor's note: Dr. Schoenfeld reports serving as a member of the speakers' bureau and as a consultant for Novartis Pharmaceuticals and GlaxoSmithKline.
References
American College of Gastroenterology Functional Gastrointestinal Disorder Task Force. Evidence-based position statement on the management of irritable bowel syndrome in North America. Am J Gastroenterol 2002;97:Suppl:S1-S5.
Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. Ann Intern Med 2000;133:136-147.
Poynard T, Regimbeau O, Benhamou Y. Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2001;15:355-361.
To the Editor: Mertz notes that individual symptoms, including abdominal pain, constipation, and diarrhea, can be treated with a variety of agents (e.g., fiber, osmotic laxatives, antispasmodic agents, and tricyclic antidepressants). In clinical practice, however, targeting the individual symptoms of irritable bowel syndrome often results in polypharmacy to achieve global symptom relief. This approach is costly and increases the likelihood of drug interactions. As Mertz notes, global symptom relief can be achieved with two readily available agents: tegaserod, a specific 5-HT4–receptor agonist, for irritable bowel syndrome with constipation,1 and alosetron, a 5-HT3–receptor antagonist, for irritable bowel syndrome with diarrhea.2 In recently published, evidence-based reviews,3,4 the American College of Gastroenterology gave these two agents the highest recommendation available on the basis of their ability to provide global relief of symptoms of irritable bowel syndrome in several high-quality clinical trials (Table 1). In contrast to Mertz's recommendations, the use of these drugs early in the treatment algorithm for irritable bowel syndrome may be both more beneficial and more cost effective than if they are reserved only for patients with severe symptoms.
Table 1. Evidence-Based Treatment Recommendations for Irritable Bowel Syndrome.
Brian E. Lacy, Ph.D., M.D.
Dartmouth–Hitchcock Medical Center
Lebanon, NH 03756
brian.lacy@hitchcock.org
Editor's note: Dr. Lacy reports participating in a research study with GlaxoSmithKline, the maker of alosetron, and having received research support in the past for basic-science projects from Novartis, the maker of tegaserod.
References
Lacy BE, Yu S. Tegaserod: a new 5-HT4 agonist. J Clin Gastroenterol 2002;34:27-33.
Cremonini F, Delgado-Aros S, Camilleri M. Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. Neurogastroenterol Motil 2003;15:79-86.
American College of Gastroenterology Functional Gastrointestinal Disorders Task Force. Evidence-based position statement on the management of irritable bowel syndrome in North America. Am J Gastroenterol 2002;97:Suppl:S1-S5.
Brandt LJ, Bjorkman D, Fennerty MB, et al. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol 2002;97:Suppl:S7-S26.
The author replies: I thank Drs. Olden, Schoenfeld, and Lacy for their comments. Drs. Schoenfeld and Lacy appropriately indicate that the data supporting the efficacy of tegaserod and alosetron for the treatment of subtypes of irritable bowel syndrome are the best available for any therapeutic agents. A purist with regard to evidence-based medicine might say that these are the only treatments that have been proved effective for irritable bowel syndrome. However, much of modern medicine has not been subjected to high-quality clinical trials. Practitioners are therefore left to decide about other therapies on the basis of existing imperfect evidence, expert consensus, and personal experience.
On the basis of such evidence, I conclude that bowel-directed therapies, antispasmodic agents, tricyclic antidepressants, and psychotherapy are effective in the treatment of irritable bowel syndrome. Whether alosetron and tegaserod are more effective remains to be proved. Although alosetron did compare favorably with an antispasmodic agent in one trial, there are risks associated with its use. Tegaserod has not yet been compared with alternative treatments (such as polyethylene glycol laxatives) for irritable bowel syndrome in which constipation predominates. Table 2 in my article includes summary information regarding antispasmodic agents, tricyclic antidepressants, tegaserod, and alosetron. Although the placement of these data in one table may create the false sense that one therapy can be compared with another, I believe that the information is useful, and I displayed it in a single table for readers' convenience. It is unknown whether wider use of tegaserod and alosetron would improve the quality of life at an acceptable price to patients and to society (depending on who is paying).
Dr. Olden points out that tegaserod is similar to, yet distinct from, cisapride. Both act as prokinetic agents, according to physiological studies and the known pharmacologic characteristics of the 5-HT4 receptor. Notably, tegaserod does not prolong the QT interval in the cardiac cycle as cisapride does and therefore has not been associated with torsade de pointes. Tegaserod appears to be effective and safe for the treatment of irritable bowel syndrome. Conversely, older agents, such as tricyclic antidepressants, appear to be effective, but side effects limit their usefulness.1 Lowering the doses of these agents may reduce their side effects.
The appropriate pharmacologic therapy for irritable bowel syndrome remains controversial, in part because of the inadequacies of previous clinical trials. Variations in the nature and severity of symptoms and coexisting conditions complicate therapeutic decisions. Accordingly, recommendations for therapy will be influenced by opinion and individual experience and by some uncertainty. Clearly, more work must be done to determine the causes of irritable bowel syndrome and the best therapy for it.
Howard Mertz, M.D.
Vanderbilt University
Nashville, TN 37235
References
Drossman DA, Toner BB, Whitehead WE, et al. Cognitive-behavioral therapy versus education and despiramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology 2003;125:19-31.
Table 1. Structural and Pharmacologic Characteristics of Tegaserod and Cisapride.
Stratifying treatment recommendations can be problematic. Studies indicate that patients' distress, when compared with the severity of individual symptoms, is important.4 The overall discomfort level, not the severity of gastrointestinal symptoms, should guide therapy. Tegaserod is approved by the Food and Drug Administration for women with irritable bowel syndrome and constipation, with no restrictions related to the severity of symptoms. The only therapy for irritable bowel syndrome that has restrictions is alosetron (used for severe irritable bowel syndrome with diarrhea), because of its safety profile and association with ischemic colitis.
Mertz correctly portrays antidepressants as efficacious for irritable bowel syndrome. However, this use of antidepressants is evolving; recent studies suggest that the side-effect profile of antidepressants affects patients' acceptance of them in important ways.5
Kevin W. Olden, M.D.
Mayo Clinic Scottsdale
Scottsdale, AZ 85259
References
Mertz HR. Irritable bowel syndrome. N Engl J Med 2003;349:2136-2146.
Morganroth J, Ruegg PC, Dunger-Baldauf C, Appel-Dingemanse S, Bliesath H, Lefkowitz M. Tegaserod, a 5-hydroxytryptamine type 4 receptor partial agonist, is devoid of electrocardiographic effects. Am J Gastroenterol 2002;97:2321-2327.
Kamm MA. The complexity of drug development for irritable bowel syndrome. Aliment Pharmacol Ther 2002;16:343-351.
Hahn BA, Kirchdoerfer LJ, Fullerton S, Mayer E. Patient-perceived severity of irritable bowel syndrome in relation to symptoms, health resource utilization and quality of life. Aliment Pharmacol Ther 1997;11:553-559.
Drossman DA, Toner BB, Whitehead WE, et al. Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology 2003;125:19-31.
To the Editor: In his review of irritable bowel syndrome, Mertz recommends fiber for irritable bowel syndrome with constipation, followed by osmotic laxatives and antispasmodic agents. He also recommends antispasmodic agents for irritable bowel syndrome in which pain predominates. This approach reflects experience-based management of the syndrome, but there may not be adequate evidence to support these recommendations.
No randomized, controlled trials have evaluated the efficacy of osmotic laxatives in patients with irritable bowel syndrome. Mertz notes that "data are lacking" to support the efficacy of fiber in these patients. These assertions are supported by a recent systematic review of the methodologic quality and results of trials of therapy for irritable bowel syndrome.1 The antispasmodic agents available in the United States (dicyclomine and hyoscyamine) have not been found to be beneficial in appropriately designed randomized, controlled trials.1 Although benefit with other antispasmodic agents has been found in meta-analyses,2,3 these trials, as Mertz states, "lacked appropriate blinding, had small numbers of patients, were of short duration, and used unclear criteria to define a clinical response." Given these methodologic limitations, it is inappropriate to report numbers needed to treat and odds ratios for therapies for irritable bowel syndrome in a single table (i.e., Mertz's Table 2).
Philip S. Schoenfeld, M.D.
University of Michigan School of Medicine
Ann Arbor, MI 48105
Editor's note: Dr. Schoenfeld reports serving as a member of the speakers' bureau and as a consultant for Novartis Pharmaceuticals and GlaxoSmithKline.
References
American College of Gastroenterology Functional Gastrointestinal Disorder Task Force. Evidence-based position statement on the management of irritable bowel syndrome in North America. Am J Gastroenterol 2002;97:Suppl:S1-S5.
Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review of randomized, controlled trials. Ann Intern Med 2000;133:136-147.
Poynard T, Regimbeau O, Benhamou Y. Meta-analysis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2001;15:355-361.
To the Editor: Mertz notes that individual symptoms, including abdominal pain, constipation, and diarrhea, can be treated with a variety of agents (e.g., fiber, osmotic laxatives, antispasmodic agents, and tricyclic antidepressants). In clinical practice, however, targeting the individual symptoms of irritable bowel syndrome often results in polypharmacy to achieve global symptom relief. This approach is costly and increases the likelihood of drug interactions. As Mertz notes, global symptom relief can be achieved with two readily available agents: tegaserod, a specific 5-HT4–receptor agonist, for irritable bowel syndrome with constipation,1 and alosetron, a 5-HT3–receptor antagonist, for irritable bowel syndrome with diarrhea.2 In recently published, evidence-based reviews,3,4 the American College of Gastroenterology gave these two agents the highest recommendation available on the basis of their ability to provide global relief of symptoms of irritable bowel syndrome in several high-quality clinical trials (Table 1). In contrast to Mertz's recommendations, the use of these drugs early in the treatment algorithm for irritable bowel syndrome may be both more beneficial and more cost effective than if they are reserved only for patients with severe symptoms.
Table 1. Evidence-Based Treatment Recommendations for Irritable Bowel Syndrome.
Brian E. Lacy, Ph.D., M.D.
Dartmouth–Hitchcock Medical Center
Lebanon, NH 03756
brian.lacy@hitchcock.org
Editor's note: Dr. Lacy reports participating in a research study with GlaxoSmithKline, the maker of alosetron, and having received research support in the past for basic-science projects from Novartis, the maker of tegaserod.
References
Lacy BE, Yu S. Tegaserod: a new 5-HT4 agonist. J Clin Gastroenterol 2002;34:27-33.
Cremonini F, Delgado-Aros S, Camilleri M. Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. Neurogastroenterol Motil 2003;15:79-86.
American College of Gastroenterology Functional Gastrointestinal Disorders Task Force. Evidence-based position statement on the management of irritable bowel syndrome in North America. Am J Gastroenterol 2002;97:Suppl:S1-S5.
Brandt LJ, Bjorkman D, Fennerty MB, et al. Systematic review on the management of irritable bowel syndrome in North America. Am J Gastroenterol 2002;97:Suppl:S7-S26.
The author replies: I thank Drs. Olden, Schoenfeld, and Lacy for their comments. Drs. Schoenfeld and Lacy appropriately indicate that the data supporting the efficacy of tegaserod and alosetron for the treatment of subtypes of irritable bowel syndrome are the best available for any therapeutic agents. A purist with regard to evidence-based medicine might say that these are the only treatments that have been proved effective for irritable bowel syndrome. However, much of modern medicine has not been subjected to high-quality clinical trials. Practitioners are therefore left to decide about other therapies on the basis of existing imperfect evidence, expert consensus, and personal experience.
On the basis of such evidence, I conclude that bowel-directed therapies, antispasmodic agents, tricyclic antidepressants, and psychotherapy are effective in the treatment of irritable bowel syndrome. Whether alosetron and tegaserod are more effective remains to be proved. Although alosetron did compare favorably with an antispasmodic agent in one trial, there are risks associated with its use. Tegaserod has not yet been compared with alternative treatments (such as polyethylene glycol laxatives) for irritable bowel syndrome in which constipation predominates. Table 2 in my article includes summary information regarding antispasmodic agents, tricyclic antidepressants, tegaserod, and alosetron. Although the placement of these data in one table may create the false sense that one therapy can be compared with another, I believe that the information is useful, and I displayed it in a single table for readers' convenience. It is unknown whether wider use of tegaserod and alosetron would improve the quality of life at an acceptable price to patients and to society (depending on who is paying).
Dr. Olden points out that tegaserod is similar to, yet distinct from, cisapride. Both act as prokinetic agents, according to physiological studies and the known pharmacologic characteristics of the 5-HT4 receptor. Notably, tegaserod does not prolong the QT interval in the cardiac cycle as cisapride does and therefore has not been associated with torsade de pointes. Tegaserod appears to be effective and safe for the treatment of irritable bowel syndrome. Conversely, older agents, such as tricyclic antidepressants, appear to be effective, but side effects limit their usefulness.1 Lowering the doses of these agents may reduce their side effects.
The appropriate pharmacologic therapy for irritable bowel syndrome remains controversial, in part because of the inadequacies of previous clinical trials. Variations in the nature and severity of symptoms and coexisting conditions complicate therapeutic decisions. Accordingly, recommendations for therapy will be influenced by opinion and individual experience and by some uncertainty. Clearly, more work must be done to determine the causes of irritable bowel syndrome and the best therapy for it.
Howard Mertz, M.D.
Vanderbilt University
Nashville, TN 37235
References
Drossman DA, Toner BB, Whitehead WE, et al. Cognitive-behavioral therapy versus education and despiramine versus placebo for moderate to severe functional bowel disorders. Gastroenterology 2003;125:19-31.