Constipation - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References 0597838429, 9780597838422, 9780585494449

Citation preview

CONSTIPATION A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

ii

ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2003 by ICON Group International, Inc. Copyright 2003 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Constipation: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-83842-9 1. Constipation-Popular works. I. Title.

iii

Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

iv

Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on constipation. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

v

About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

vi

About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes & Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

vii

Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON CONSTIPATION ......................................................................................... 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Constipation................................................................................ 23 The National Library of Medicine: PubMed ................................................................................ 44 CHAPTER 2. NUTRITION AND CONSTIPATION ............................................................................... 89 Overview...................................................................................................................................... 89 Finding Nutrition Studies on Constipation................................................................................. 89 Federal Resources on Nutrition ................................................................................................... 98 Additional Web Resources ........................................................................................................... 99 CHAPTER 3. ALTERNATIVE MEDICINE AND CONSTIPATION ....................................................... 103 Overview.................................................................................................................................... 103 The Combined Health Information Database............................................................................. 103 National Center for Complementary and Alternative Medicine................................................ 104 Additional Web Resources ......................................................................................................... 120 General References ..................................................................................................................... 137 CHAPTER 4. CLINICAL TRIALS AND CONSTIPATION .................................................................... 139 Overview.................................................................................................................................... 139 Recent Trials on Constipation ................................................................................................... 139 Keeping Current on Clinical Trials ........................................................................................... 140 CHAPTER 5. PATENTS ON CONSTIPATION .................................................................................... 143 Overview.................................................................................................................................... 143 Patents on Constipation............................................................................................................. 143 Patent Applications on Constipation ......................................................................................... 164 Keeping Current ........................................................................................................................ 184 CHAPTER 6. BOOKS ON CONSTIPATION........................................................................................ 185 Overview.................................................................................................................................... 185 Book Summaries: Federal Agencies............................................................................................ 185 Book Summaries: Online Booksellers......................................................................................... 186 The National Library of Medicine Book Index ........................................................................... 188 Chapters on Constipation........................................................................................................... 190 Directories.................................................................................................................................. 193 CHAPTER 7. MULTIMEDIA ON CONSTIPATION ............................................................................. 195 Overview.................................................................................................................................... 195 Video Recordings ....................................................................................................................... 195 Bibliography: Multimedia on Constipation ............................................................................... 196 CHAPTER 8. PERIODICALS AND NEWS ON CONSTIPATION .......................................................... 197 Overview.................................................................................................................................... 197 News Services and Press Releases.............................................................................................. 197 Newsletters on Constipation...................................................................................................... 199 Newsletter Articles .................................................................................................................... 200 Academic Periodicals covering Constipation ............................................................................. 202 CHAPTER 9. RESEARCHING MEDICATIONS .................................................................................. 205 Overview.................................................................................................................................... 205 U.S. Pharmacopeia..................................................................................................................... 205 Commercial Databases ............................................................................................................... 206 Researching Orphan Drugs ....................................................................................................... 207 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 211 Overview.................................................................................................................................... 211 NIH Guidelines.......................................................................................................................... 211

viii Contents

NIH Databases........................................................................................................................... 213 Other Commercial Databases..................................................................................................... 217 APPENDIX B. PATIENT RESOURCES ............................................................................................... 219 Overview.................................................................................................................................... 219 Patient Guideline Sources.......................................................................................................... 219 Finding Associations.................................................................................................................. 230 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 233 Overview.................................................................................................................................... 233 Preparation................................................................................................................................. 233 Finding a Local Medical Library................................................................................................ 233 Medical Libraries in the U.S. and Canada ................................................................................. 233 ONLINE GLOSSARIES................................................................................................................ 239 Online Dictionary Directories ................................................................................................... 241 CONSTIPATION DICTIONARY............................................................................................... 243 INDEX .............................................................................................................................................. 313

1

FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with constipation is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about constipation, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to constipation, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on constipation. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to constipation, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on constipation. The Editors

1

From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

3

CHAPTER 1. STUDIES ON CONSTIPATION Overview In this chapter, we will show you how to locate peer-reviewed references and studies on constipation.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and constipation, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “constipation” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Diarrhea-Constipation-Pain: When is It Irritable Bowel Syndrome? Source: Consultant. 41(8): 1089-1091, 1095-1096. July 2001. Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: Central to the diagnosis of irritable bowel syndrome (IBS) are the symptoms of abdominal pain and disordered defecation of at least 3 months' duration. This article helps physicians determine when the symptoms of diarrhea, or constipation, or pain are indeed due to IBS. Either diarrhea or constipation can predominate, although the defecation pattern may vary from day to day in some patients. In the absence of evidence of more serious disease, diagnosis is based largely on the results of a thorough history and examination. For most patients, general screening tests include a complete

4

Constipation

blood cell count, erythrocyte sedimentation rate, serum chemistry panel, stool guaiac test, and stool examination for ova (eggs) and parasites. For patients older than 50 years, flexible sigmoidoscopy, colonoscopy, or barium enema may be indicated. Management of IBS consists of patient education and reassurance; dietary modification, including increased fiber intake in patients with constipation; and in some cases, judicious use of medications or psychological interventions. 2 tables. 35 references. •

Correcting Constipation: A Regimen That Works Source: Senior Patient. 3(1): 37-41. January-February 1991. Summary: Chronic, untreated constipation can cause abdominal discomfort and rectal pain or tenesmus, and can lead to fecal impaction, fecal and urinary incontinence, and volvulus. This article presents a regimen for correcting constipation that moves the focus away from chronic use of laxatives in high dosages. Topics discussed include the importance of taking a detailed patient history, the physical examination and lab work required for diagnosis, the definitions and causes of constipation, starting treatment, notably for fecal impaction, and the roles of fluid intake, diet, exercise, and private toilet facilities in managing chronic constipation. A recipe for an easy-to-prepare supplement, to use as a source of fiber and a colonic stimulant, is included. 2 figures. 2 tables. 10 references.

•

Constipation in the Elderly Source: American Family Physician. 58(4): 907-914. September 15, 1998. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: Constipation affects as many as 26 percent of older men and 34 percent of older women and is a problem that has been related to diminished perception of quality of life. This article reviews the problem of constipation in older people and encourages family physicians to learn about and address this problem in their patients. Constipation may be a sign of a serious problem such as a mass lesion, a manifestation of a systemic disorder such as hypothyroidism, or a side effect of medications such as narcotic analgesics. The patient with constipation should be questioned about fluid and food intake, medications, supplements, and homeopathic remedies. The physical examination may reveal local masses or thrombosed hemorrhoids, which may be contributing to the constipation. Visual inspection of the colon is useful when no obvious cause of constipation can be determined. Treatment should address the underlying abnormality. The chronic use of certain treatments, such as laxatives, should be avoided. First-line therapy should include bowel retraining, increased dietary fiber and fluid intake, and exercise when possible. Laxatives, stool softeners, and nonabsorbable solutions may be needed in some patients with chronic constipation. 1 figure. 4 tables. 17 references. (AAM).

•

Functional Childhood Constipation: A Practical Approach Source: Practical Gastroenterology. 23(12): 16, 20-22, 24-26, 33-34. December 1999. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: Constipation is a common childhood problem and is frequently encountered by the primary care physician and the pediatric gastroenterologist alike. Although the presentation of constipation in infancy raises concerns about organic etiologies, the large

Studies

5

majority of infantile and childhood presentations of constipation have a functional basis. This review article emphasizes the concepts basic to the recognition and management of functional childhood constipation from the perspective of a primary care physician. Data obtained through a careful history and physical examination should enable the physician in most cases to confidently establish the diagnosis of functional constipation and exclude less common organic disorders. Infants and older children with atypical features or intractable constipation may require diagnostic investigations. Most children recover satisfactorily after being managed with a combination of incentive based behavior modification and stool softeners. The authors note that early recognition and initiation of behavior modification and pharmacotherapy in children favorably influences prognosis. Children with intractable constipation and those suspected of having underlying organic etiologies can therefore be identified by the primary care physician and referred to a subspecialist for further evaluation. 1 figure. 3 tables. 15 references. •

Therapy of Constipation Source: Alimentary Pharmacology and Therapeutics. 15(6): 749-763. June 2001. Contact: Available from Alimentary Pharmacology and Therapeutics. Blackwell Science Ltd., Osney Mead, Oxford OX2 OEL, UK. +44(0)1865 206206. Fax +44(0)1865 721205. Email: [email protected]. Website: www.blackwell-science.com. Summary: Constipation is a common symptom that may be idiopathic (of unknown cause) or due to various identifiable disease processes. This article reviews the current recommendations for treating constipation. Laxatives are agents that add bulk to intestinal contents, that retain water within the bowel lumen by virtue of osmotic effects, or that stimulate intestinal secretion or motility, thereby increasing the frequency and ease of defecation. Drugs which improve constipation by stimulating gastrointestinal motility (movement) by direct actions on the enteric nervous system are under development. Mineral oil is a lubricating agent that facilitates defecation by altering stool consistency and by forming a slippery layer around fecal pellets. Other modalities used to treat constipation include biofeedback and surgery. Laxatives and lavage (cleaning) solutions are also used for colon preparation and evaluation of the bowels after toxic ingestions. Most patients with constipation will try to treat this condition themselves before seeking medical attention. Therefore, it is important for the health care provider to obtain a good history of the treatments that have been tried previously in addition to trying to develop a good understanding of exactly what problems the patient is having with defecation. A detailed physical examination, including a thorough rectal examination is also important. 3 tables. 133 references.

•

Constipation Management: An In-Service Source: Journal of Nurse Assistants. p. 28-29, 32. July 2000. Contact: Available from Journal of Nurse Assistants. P.O. Box 23365, Chagrin Falls, OH 44023. (440) 247-5668. Fax (440) 247-8925. Summary: Constipation is a very common problem among the elderly. This article helps nurse assistants to understand the causes of constipation and the current recommendations for managing constipation in the elderly population, particularly those living in long term care facilities. The author first discusses the impact of aging on the gastrointestinal system, the problems associated with less exercise and activity, the continued need for adequate hydration (consumption of fluids), the use of medications that may cause or worsen constipation, changes in nutrition and food habits, and the

6

Constipation

impact of alcohol abuse. The author defines constipation as a delay in the routine of defecation, or the elimination of hard dry stool. Nursing facilities often cite a three day limit without stools as the guideline for intervention. The author describes three general types of constipation: atonic (weakness of the muscles of the colon and rectum), obstructive (blockage of the intestines), and spastic (contraction of the muscles of the intestinal wall). The goal for any treatment of the patient with constipation is to develop a regular pattern of bowel elimination and develop methods to prevent constipation. The nurse assistant and home health assistant should learn the patient's bowel pattern and help the patient keep to the pattern. In addition, patients should be encouraged to eat foods that contain fiber, such as fruits and vegetables, grains and cereals. It is essential to provide for privacy and time to defecate. Bedpan use should be avoided if possible. Appropriate hygiene for hands and perineal skin after bowel movements is essential. The author concludes that there are many things that the nurse assistant can do to promote successful elimination. Attention to routines, documentation of results, and reporting to the charge nurse are vital to maintaining normal bowel habits for the residents. Appended to the article is an inservice quiz for readers to test the knowledge gained from reading the article. •

Methylnaltrexone for Reversal of Constipation Due to Chronic Methadone Use: A Randomized Controlled Trial Source: JAMA. Journal of American Medical Association. 283(3): 367-372. January 19, 2000. Summary: Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient. This article reports on a study undertaken to evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone induced constipation. The double blind, randomized placebo controlled trial was conducted between May 1997 and December 1998 at the clinical research center of a university hospital. The subjects (n = 22, 9 men and 13 women) had a mean age of 43.2 years and were enrolled in a methadone maintenance program and had methadone induced constipation. The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration. The oral cecal transit times at baseline for subjects in the treatment and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (standard deviation) change in the treatment group was minus 77.7 minutes, significantly greater than the average change in the placebo group of minus 1.4 minutes. No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study. The authors conclude that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal transit time in subjects taking high opioid dosages. Low dosage methylnaltrexone may have clinical utility in managing opioid induced constipation. 3 figures. 1 table. 37 references.

•

Chronic Constipation in Adults: How Far Should Evaluation and Treatment Go? Source: Postgraduate Medicine. 88(3): 49-50, 57-59, 63. September 1, 1990. Summary: Constipation needs to be evaluated in all patients who complain of infrequent or difficult bowel movements. This article outlines the diagnostic effort that should be expended, depending on the patient's age, duration, and severity of constipation, and presence of concomitant symptoms. The author also offers advice on

Studies

7

treating constipation that is primarily functional. The author stresses that structural evaluation of the entire colon by barium enema should be considered when constipation is of recent onset, is severe, or does not resolve with simple measures. One sidebar illustrates the anatomical function of normal defecation. The author also lists some bulkforming agents and laxatives for treating constipation. 2 figures. 21 references. (AA-M). •

Constipation and Fecal Incontinence in the Elderly Source: Gastroenterology Clinics of North America. 30(2): 497-515. June 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: Continence and defecation are complex functions that require the interaction of visceral and pelvic muscles and the nerves that regulate their activity. These activities may be abnormal in elderly patients and can produce symptoms, such as chronic constipation or fecal incontinence (involuntary loss of stool). This article, from a special issue on gastrointestinal (GI) disorders in the elderly, addresses constipation and fecal incontinence in this population. The author emphasizes that, contrary to widespread opinion, much can be done to improve constipation and incontinence in the elderly and relieve a considerable burden in these patients. Relatively little research has been done to differentiate physiologic changes in rectoanal function resulting from aging and pathologic changes resulting from diseases occurring as patients age. Treatment includes identification and treatment of the underlying disease, if possible, protective skin care, continence aids, psychologic support, drug therapy (for stimulation of defecation at intervals, antidiarrheal drugs), biofeedback, and surgical therapy. Results of therapy often can be good, leading to alleviation of suffering and the ability to lead a fuller life. 1 figure. 4 tables. 92 references.

•

Functional Constipation Source: Seminars in Pediatric Surgery. 4(1): 26-34. February 1995. Contact: Available from W.B. Saunders Company. Curtis Center, Independence Square West, Philadelphia, PA 19106-3399. (800) 654-2452. Summary: In this article, the author explains the differential diagnosis of constipation in childhood; develops an algorithm for the evaluation of children with severe constipation to identify patients who need surgical therapy or might benefit from surgical therapy; outlines the nonsurgical treatment of constipation; and reports on treatment outcome in children with functional constipation. The treatment program for functional constipation includes various forms of behavioral therapy and psychological approaches, and consists of education, disimpaction, prevention of reaccumulation of stools with fiber and laxatives, and reconditioning to normal bowel habits with frequent toileting. 4 figure. 1 table. 47 references. (AA-M).

•

Chronic Constipation in Children Source: Gastroenterology. Volume 105(5): 1557-1564. November 1993. Summary: In this article, the author reviews chronic constipation in children. The author describes the symptoms of chronic constipation in infants and older children; presents the differential diagnosis and algorithms for the evaluation of these children; and explains treatment and treatment outcomes. She notes that constipation in very young children and in older children differs considerably from that in adults. Most patients will benefit from a program designed to clear stools, to prevent further impaction, and

8

Constipation

to promote regular bowel habits. Fifty percent of patients will be cured after 1 year and 65 to 70 percent after two years. 2 figures. 2 tables. 61 references. (AA-M). •

Chronic Idiopathic Constipation: Pathophysiology and Treatment Source: Journal of Clinical Gastroenterology. 22(3): 190-196. April 1996. Summary: In this article, the authors consider the pathophysiology and treatment of chronic idiopathic constipation, a common occurrence in the general population, especially in women. Topics include the need for more consistent definitions and terminology, the primary and secondary forms of constipation, the clinical and pathophysiological patterns of slow-transit constipation and normal-transit constipation, treatment issues, dietary and pharmacologic treatment, psychological and behavioral treatment, and surgical treatment. The authors conclude that conservative nonsurgical measures, including biofeedback, are indicated for the great majority of constipated patients, whereas more aggressive (surgical) options are available for a distinct and increasingly identifiable minority of patients with disabling and intractable symptoms. 2 tables. 92 references. (AA-M).

•

Constipation and Fecal Incontinence in the Elderly Population Source: Mayo Clinic Proceedings. 71(1): 81-92. January 1996. Summary: In this article, the authors describe the assessment and management of constipation and fecal incontinence in elderly patients. The authors review the recent medical literature and outline management strategies for these problems. Constipation is classified into two syndromes: functional constipation and rectosigmoid outlet delay. Evaluation consists of a detailed history, directed physical examination, and selected laboratory tests. Management involves nonpharmacologic (such as exercise and fiber) and pharmacologic measures. Fecal incontinence in elderly patients can be due to stool impaction, medications, dementia, or neuromuscular dysfunction. The authors stress that management of these disorders should be highly individualized and dependent on cause, coexisting morbidities, and cognitive status. 10 tables. 73 references. (AA-M).

•

Functional Colonic and Anorectal Disorders: Detecting and Overcoming Causes of Constipation and Fecal Incontinence Source: Postgraduate Medicine. 98(5): 115-119, 124-126. November 1995. Summary: In this article, the fourth of four articles on diseases of the colon, the author discusses functional colonic and anorectal disorders, notably constipation and fecal incontinence. The author encourages readers to overcome reluctance to discuss defecation disorders and pursue thorough history taking. The author summarizes methods for determining the underlying cause of these disorders and describes approaches to management to help restore confidence and dignity to patients. Readers can qualify for continuing medical education credits by completing the posttest after the article. 1 figure. 1 table. 40 references. (AA-M).

•

Increasing Oral Fluids in Chronic Constipation in Children Source: Gastroenterology Nursing. 21(4): 156-161. July-August 1998. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (410) 528-8555.

Studies

9

Summary: Increasing the amount and type of fluid intake in children with simple constipation remains a common intervention recommended by both the medical profession and lay consumers. However, there is no research or physiologic basis for increasing overall water intake and or high osmolarity liquid intake in order to produce softer or more frequent stools. This article reports on a project undertaken to identify whether a concerted effort to increase liquid intake would lead to an effect on stooling characteristics. Ninety children completed the entire study as assigned (59 girls, 31 boys). Neither increasing water intake nor increasing hyperosmolar liquid intake significantly increased stool frequency or decreased consistency or difficulty with passage. The authors conclude that nurses need to be proactive in changing commonly held thoughts regarding the treatment of pediatric constipation. Advising new parents of what is acceptable in stooling patterns is important. Encouraging a high insoluble fiber intake is more beneficial in promoting healthy stool patterns than any amount of increased liquid intake. Advising parents of constipated children to increase liquid intake is not helpful and should not be recommended unless history suggests that the child's liquid intake is inadequate for a normal child of that age and activity level. 3 figures. 4 tables. 19 references. (AA-M). •

Chronic Idiopathic Constipation: A Psychological Enquiry Source: European Journal of Gastroenterology and Hepatology. 13(1): 39-44. January 2001. Contact: Available from Lippincott Williams and Wilkins. 241 Borough High Street, London SE1 1GB, UK 44(0)20-7940-7502. Fax: 44(0)20-7940-7574. Website: http://www.eurojgh.com/. Summary: Intractable idiopathic (of undetermined cause) constipation in women is often associated with psychosocial problems. This article reports on a study undertaken to determine the past and current psychological factors associated with slow and normal transit constipation. Consecutive female patients (n = 28) referred for biofeedback treatment were interviewed before the procedure. Transit studies revealed that 12 had slow transit constipation (STC) and 16 had normal transit constipation (NTC). Patients were assessed for evidence of previous and current psychiatric diagnoses; family and social history was noted; and self-rating scales were used to measure psychological distress, abnormal attitudes to eating, and current psychosocial functioning. The mean age of the 28 patients was 38.2 years (plus or minus 10.8 years) with a mean duration of symptoms of 17.6 years (plus or minus 16.9 years). Seventeen (61 percent) had a current psychiatric disorder and 18 (64 percent) a previous episode of psychiatric illness. The mean age of the 16 NTC patients was 38.4 years (plus or minus 10.1 years) with a mean duration of symptoms of 12.4 years (plus or minus 15.9 years). By contrast, the 12 STC patients had a much longer mean duration of constipation (24.3 years; plus of minus 16.4 years), a mean age of 37.9 years (plus of minus 12.1 years), with half having an onset in childhood. The STC patients reported more psychosocial distress on the rating scales than those with NTC, and only one did not experience some form of adverse life event or gynecological procedure in the 6 months before the onset of constipation. Eleven (39 percent) of the 28 women had had a hysterectomy at a mean age of 36 years, but only four (14 percent) reported a history of sexual abuse. Of the nine (32 percent) patients who reported markedly distorted attitudes to food, six had NTC and three had STC. The authors conclude that although STC is a chronic disorder accompanied by high rates of psychological distress, it does not appear to be associated with gross functional impairment. The authors suggest that patients who present to surgical

10

Constipation

departments with chronic intractable constipation should routinely have a psychological assessment. 2 figures. 3 tables. 31 references. •

Randomized, Double-blind, Placebo-Controlled Trial of Tegaserod in Female Patients Suffering from Irritable Bowel Syndrome With Constipation Source: Alimentary Pharmacology and Therapeutics. 16(11): 1877-1888. November 2002. Contact: Available from Alimentary Pharmacology and Therapeutics. Blackwell Science Ltd., Osney Mead, Oxford OX2 OEL, UK. +44(0)1865 206206. Fax +44(0)1865 721205. Email: [email protected]. Website: www.blackwell-science.com. Summary: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which affects up to 20 percent of the population, with a predominance in females. This article reports on a study undertaken to evaluated the effectiveness and safety of the drug tegaserod in female patients with IBS characterized by symptoms of abdominal pain or discomfort and constipation. In the randomized, double-blind, multicenter study, 1519 women received either tegaserod, 6 milligrams twice a day (n = 767), or placebo (n = 752) for 12 weeks, preceded by a 4 week baseline period without treatment and followed by a 4 week open withdrawal period. The primary effectiveness evaluation was the patient's symptomatic response as measured by the Subject's Global Assessment of Relief. Other efficacy variables included abdominal pain or discomfort, bowel habits, and bloating. Results showed that tegaserod produced significant improvements in the Subject's Global Assessment of Relief and other efficacy variables. These improvements were seen within the first week, and were maintained throughout the treatment period. After withdrawal of treatment, the symptoms rapidly returned. Overall, tegaserod was well tolerated. Diarrhea was the most frequent adverse event; however, this led to discontinuation in only 1.6 percent of tegaserod-treated patients. The authors conclude that tegaserod produced rapid and sustained improvement of symptoms in female irritable bowel syndrome patients and was well tolerated. 4 figures. 2 tables. 31 references.

•

Childhood Constipation: Finally Some Hard Data About Hard Stools! (editorial) Source: Journal of Pediatrics. 136(1): 4-7. January 2000. Contact: Available from Mosby, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-3318. (800) 453-4351 or (314) 453-4351. Fax (314) 432-1158. Website: www.mosby.com. Summary: It is estimated that 55 million adults in the United States (approximately 28 percent of the population) are constipated. Similar data are not available on the prevalence in children, although it has been reported that 34 percent of toddlers in the United Kingdom and 37 percent of Brazilian children younger than 12 were considered by their parents to be constipated. This editorial offers a review of the literature on childhood constipation, focusing on research studies that quantified the prevalence of the problem. The editorial also serves as an introduction to two related articles in the same issue of Journal of Pediatrics. The author notes that the most common cause of constipation in pediatrics is a decision made by the child to delay defecation after experiencing a painful or frightening evacuation. Treatment is based on addressing all the factors that have contributed to its development. The evacuations are made more pleasant by stool softeners. The fear of defecation is overcome by avoiding anally invasive procedures (such as enemas) and by using positive reinforcement to make the process less intimidating. Key to successful treatment is a thorough understanding by the family of the pathophysiology of childhood constipation. The author applauds the

Studies

11

authors of the other articles for addressing this poorly studied subject. Progress in the understanding of colonic motility disorders and the pathophysiologic mechanisms responsible for treatment failures will help in the selection of patients who may benefit from the use of cisapride and dietary changes. Development of safe prokinetics with a more selective action on colonic motility will undoubtedly facilitate their use in the treatment of childhood constipation. 12 references. •

Prucalopride, a Systemic Enterokinetic, for the Treatment of Constipation Source: Alimentary Pharmacology and Therapeutics. 16(7):1347-1356. July 2002. Contact: Available from Alimentary Pharmacology and Therapeutics. Blackwell Science Ltd., Osney Mead, Oxford OX2 OEL, UK. +44(0)1865 206206. Fax +44(0)1865 721205. Email: [email protected]. Website: www.blackwell-science.com. Summary: Laxatives are frequently ineffective in treating constipation. An alternative therapeutic approach is to target serotonin 4 receptors, which are involved in initiating peristalsis. This article reports on a study undertaken to assess the effectiveness and safety of a systemically active serotonin 4 agonist, prucalopride. In the study, 74 women with constipation were stratified into slow or normal transit groups, and each group was randomized to receive either placebo or 1 milligram prucalopride daily for 4 weeks. Prucalopride, not placebo, increased spontaneous stool frequency and reduced time to first stool. Prucalopride reduced the number of retained markers in all patients compared to placebo. Prucalopride reduced the mean number of retained markers in slow transit, but did not alter the marker count in normal transit. Orocecal transit was accelerated by prucalopride, not placebo. Prucalopride, not placebo, increased rectal sensitivity to distension and electrical stimulation. Prucalopride significantly improved several domains of the Short Form Health Status Survey and the disease specific quality of life. Adverse effects were similar for prucalopride and placebo. 1 figure. 3 tables. 39 references.

•

Constipation in Imperforate Anus Source: Pull-Thru Network News. 8(1): 1-2. February 1999. Contact: Available from Pull-Thru Network. 4 Woody Lane, Westport, CT 06880. Summary: Most of the patients who are born with imperforate anus and undergo a repair that preserves their rectum will be constipation. This newsletter article reviews the problem, which seems to be the clinical manifestation of a hypomotility disorder of the rectosigmoid colon. After colostomy closure, proper treatment of the constipation is imperative. When it is not treated properly (meaning that the rectum is emptied every day), the megasigmoid worsens. The author notes that constipation can be a serious problem because it eventually provokes fecal incontinence, even in patients who were born with a potential for bowel control. The author also discusses the diagnosis of Hirschsprung's disease and imperforate anus, stressing that this condition is overdiagnosed. Patients with poor potential for bowel control and constipation should be treated with an enema every day, with close monitoring until the regimen is established. Patients with a good potential for bowel control and constipation should be treated with laxatives; however, it is important to establish the proper amount of laxatives for the individual patient. The author concludes with a brief discussion of the complication of tethered cord.

12

Constipation

•

Outpatient Quality Assurance Monitor: Constipation/Encopresis Source: Gastroenterology Nursing. 17(2): 57-60. September-October 1994. Summary: Quality Assurance (QA) programs assure that patients get the appropriate care, information, and support needed to produce better health outcomes. In this article, the authors describe monitoring the nursing process by documentation of care in patients with constipation and encopresis. Topics include treatment methods used to monitor the health care; data collection; and a discussion, including recommendations for other facilities hoping to undertake a QA program. The authors also employed a longitudinal follow-up to monitor patient outcomes. They note that the process portion of the monitor program was very successful, but the results of the outcome monitor were disappointing. 2 figures. 2 tables. 5 references. (AA-M).

•

Chronic Constipation: Causes and Management Source: Hospital Practice. p. 89-100. April 30, 1990. Summary: Since the term constipation represents symptoms rather than a disease, an individual's definition of constipation is bound to be highly subjective. This article discusses the causes and management of chronic constipation. The author describes three syndromes with unidentified causes: idiopathic chronic constipation; irritable bowel syndrome; and idiopathic intestinal pseudo-obstruction. The author also discusses some identifiable causes of constipation, including: dietary factors and physical inactivity, diabetes mellitus, drug-induced constipation, and specific motility disorders. Three final sections cover the diagnostic approach, medical treatment, and surgical treatment for chronic constipation. 2 tables. 2 figures. 6 references.

•

Slow Transit Constipation: A Disorder of Pelvic Autonomic Nerves? Source: Digestive Diseases and Sciences. 46(2): 389-401. February 2001. Contact: Available from Kluwer Academic/Plenum Publishers. 233 Spring Street, New York, NY 10013-1578. (212) 620-8000. Fax (212) 807-1047. Summary: Slow transit constipation (STC) is a severe motility disorder, which in the majority of cases is of unknown etiology. In some patients, symptoms arise in childhood, but a proportion of patients present in later life, including after pelvic surgery or childbirth. In this article, the authors describe the current knowledge of the anatomy and function of the pelvic autonomic nerves with respect to colonic motility (experimental and observational studies); discuss evidence for pelvic nerve injury in STC arising after pelvic surgery or childbirth; and, on the basis that such patients are clinically indistinguishable from patients with chronic idiopathic (of unknown cause) STC, to evaluate whether there is evidence that pelvic autonomic neuropathy (nerve damage or disease) has an etiologic role in patients with chronic idiopathic STC. The authors document the clear importance of the pelvic autonomic nerves in colonic motor function. While there is an association between pelvic surgery and childbirth, and the onset of STC, there is little direct anatomical evidence that pelvic denervation occurs in these patients. However, the phenotype of these patients is similar to results of experimental and observational studies. The authors present evidence for possible pathogenetic mechanisms underlying the pelvic autonomic neuropathy in chronic idiopathic STC. 1 figure. 3 tables. 162 references.

Studies

•

13

American Gastroenterological Association Medical Position Statement: Guidelines on Constipation Source: Gastroenterology. 119(6): 1761-1766. December 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: Symptoms of constipation are extremely common; the prevalence has been reported to be as high as 20 percent. Many people seek medical care for constipation, but fortunately, most do not have a life threatening or disabling disorder, and the primary need is for control of symptoms. This document presents the official recommendations of the American Gastroenterological Association (AGA, May 2000) on managing patients with constipation. Recommendations focus on more rational and less invasive diagnostic approaches, and more rational and effective therapies that will improve the patient's quality of life; both of these approaches should have beneficial fiscal and logistic impacts on the health care system. The document first defines constipation and its clinical subgroups, including slow transit constipation (colonic inertia), pelvic floor dysfunction, and combination syndromes, then reviews the recommended clinical evaluation of the patient who presents with constipation. The remainder of the document briefly reviews the diagnostic tests, medical management, and the place of surgery and pelvic floor retraining programs for this patient population. 3 figures. 1 reference.

•

Long-term Safety of Tegaserod in Patients with Constipation-Predominant Irritable Bowel Syndrome Source: Alimentary Pharmacology and Therapeutics. 16(10): 1701-1708. October 2002. Contact: Available from Alimentary Pharmacology and Therapeutics. Blackwell Science Ltd., Osney Mead, Oxford OX2 OEL, UK. +44(0)1865 206206. Fax +44(0)1865 721205. Email: [email protected]. Website: www.blackwell-science.com. Summary: The oral administration of the drug tegaserod causes gastrointestinal (GI) effects resulting in increased gastrointestinal motility (movement of contents through the GI tract) and attenuation of visceral sensation. This article reports on a study undertaken to determine the long term safety and tolerability of tegaserod in patients with irritable bowel syndrome (IBS) with constipation as the predominant symptom of altered bowel habits. The multicenter, open label study included 579 patients. Of these, 304 (53 percent) completed the trial. The most common adverse events, classified as related to tegaserod for any dose, were mild and transient diarrhea (10.1 percent), headache (8.3 percent), abdominal pain (7.4 percent), and flatulence (5.5 percent). Forty serious adverse events were reported in 25 patients (4.4 percent of patients) leading to discontinuation in 6 patients. There was one serious adverse event, acute abdominal pain, classified as possibly related to tegaserod. There were no consistent differences in adverse events between patients previously exposed to tegaserod and those treated for the first time in this study. The authors conclude that tegaserod appears to be well tolerated in the treatment of patients with constipation-predominant IBS. The adverse event profile, clinical laboratory evaluations, vital signs, and electrocardiogram recordings revealed no evidence of any unexpected adverse events, and suggest that treatment is safe over a 12 month period. 1 figure. 4 tables. 23 references.

•

Use of Soluble Fiber in Constipation-Predominant IBS: A Non-Controversy Source: Practical Gastroenterology. 20(9): 64, 66-68, 70. September 1996.

14

Constipation

Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article defines the use of soluble fiber in constipation predominant irritable bowel syndrome (IBS). The author contends that the physiologic and clinical evidence confirms the value of soluble fiber in the treatment of this condition. When soluble fiber is appropriately employed as a dietary supplement in graded doses with adequate fluid intake, benefit may be seen in the form of increased stool weight, improved consistency of stools, reduced transit time, better-lubricated stools, and improved rectal satisfaction. The author stresses that close attention must be given to variations in individual diets, particularly with regard to total intake of 'natural' fiber. The dose of dietary fiber should be adjusted to each patient's response, allowing enough time to evaluate that response effectively. Practitioners should also distinguish between excessive rectal gas (which indicates excessive gas production) and feelings of bloating (which are usually unrelated to excessive gas production). 19 figures. (AA-M). •

Anorectal Manometry, EMG, Defecography and Colonic Transit Studies to Evaluate Constipation Source: Practical Gastroenterology. 23(8): 52, 54, 58, 60, 62. August 1999. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article discusses tests used to evaluate constipation, including anorectal manometry, electromyography, defecography, and colonic transit studies. Anorectal manometry provides information about the pressure activity of the rectum and the anal canal, together with an evaluation of the rectal sensation, the recto anal reflexes, and the rectal compliance. Electromyography (EMG) is used in the investigation of the internal and external sphincters as well as pelvic floor muscles. Defecography is the functional fluroscopic evaluation of rectal emptying, using both fluoroscopy and videotape. Defecography clearly defines the anorectal angle and its paradoxical increase in pelvic floor dyssynergia. The colonic transit study is most helpful in evaluating a constipated patient with infrequent defecation. This test can use scintigraphy, a single marker bolus technique, or a multiple marker bolus technique. Colonic transit studies can distinguish between colonic inertia and outlet delay. The author stresses that accurate diagnosis can then result in specific treatment being offered and succeeding. 3 figures. 1 table. 10 references.

•

Constipation, Part II: Remedies Source: Harvard Health Letter. 16(5): 5-6. March 1991. Summary: This article discusses the various treatments for constipation. The author stresses that people with essentially normal bowel function who are going through a period of transitory discomfort can probably help themselves most effectively by increasing their dietary fiber intake, drinking plenty of water, and getting moderate amounts of exercise. For each of these measures, the author considers the advantages, disadvantages, and arguments supporting or rejecting their use. The author also discusses laxatives, suppositories, enemas, and surgery as treatment for constipation. One sidebar details four categories of oral laxatives.

•

Treating Constipation in the Patient With Diabetes Source: Diabetes Educator. 21(3): 223-232. May-June 1995.

Studies

15

Contact: Available from American Association of Diabetes Educators. 444 North Michigan Avenue, Suite 1240, Chicago, IL 60611-3901. (312) 644-2233. Summary: This article explains how to treat constipation in the patient with diabetes. These patients have a significant risk of developing severe constipation, often due to dysfunction of the autonomic nervous system. The author addresses epidemiology and risk factors; the clinical features of constipation; patient evaluation; the pathophysiology of constipation in diabetes; and treatment options, including nonpharmacologic and lifestyle interventions, and drug treatment. Four tables summarize the disorders commonly associated with constipation; drugs that may cause constipation; food sources of dietary fiber; and the pharmacologic treatments for constipation. The author concludes that prokinetic agents, particularly cisapride, provide a legitimate choice when more conservative management has failed and should be considered second line therapy in the patient with diabetes who has evidence of autonomic dysfunction. 5 tables. 43 references. (AA-M). •

Hirschsprung's Disease: A Cause of Chronic Constipation in Children Source: American Family Physician. 51(2): 487-494. February 1, 1995. Summary: This article for primary care physicians explains the problem of Hirschsprung's disease as a cause of chronic constipation in children. Hirschsprung's disease is characterized by an absence of the intramural ganglionic cells at the submucosal and myenteric levels of the intestine. The course of the disease is variable, with five distinct patterns of varying severity. Without treatment, mortality approaches 50 percent by one year of age, but early diagnosis and intervention are associated with a favorable outcome. Topics include definition, etiology, clinical course, differential diagnosis, treatment, and prognosis. A brief case report is presented. The authors also review the surgical treatment involved. 3 figures. 6 tables. 24 references. (AA-M).

•

Dealing with Irregularity: Constipation, Diarrhea, Excessive Gas and Foul-Smelling Gas Source: Digestive Health and Nutrition. 3(1): 16-20. January-February 2001. Contact: Available from American Gastroenterological Association. 7910 Woodmont Avenue, 7th Floor, Bethesda, MD 20814. (877) DHN-4YOU or (301) 654-2055, ext. 650. Email: [email protected]. Summary: This article offers strategies for dealing with problems of bowel irregularity, including constipation, diarrhea, excessive gas, and foul-smelling gas. The author notes that bowel habits vary greatly among individuals, so each person's perception of whether there even is a problem and how to deal with it best is different. The author stresses that too little fiber and liquid in the diet are by far the most common reasons for constipation among people living in western cultures. The fiber found in foods such as fruits, grains, and vegetables adds bulk to the stool, making it easier to move through the colon (large intestine). Liquids add both bulk and fluid to the stool. Exercise helps prevent constipation by maintaining energy levels and promoting intestinal activity. A number of pain medications; antidepressants; antacids that contain aluminum; diuretics; and antiinflammatory and antiseizure medications are some of the many medications that can contribute to constipation. Changes in routines can also cause irregularity. The author explores the role of aging as a cause of constipation. Laxatives are an effective remedy for constipation, but they should be used with caution. As with constipation, diarrhea means different things to different people. Bacterial and viral infections are the most common causes of acute diarrhea; food intolerance is another frequent cause of

16

Constipation

both diarrhea and gas. Regardless of the cause, diarrhea usually lasts only a few days and ends on its own without the need for medical attention. The author reviews the concerns regarding dehydration, which can be a consequence of diarrhea, particularly in children and in the elderly. Gas comes from two sources: swallowed air and the breakdown of certain undigested foods in the large intestine. Simple ways of reducing the gas from swallowed air include eating and drinking more slowly, not chewing gum, and having dentures properly fitted. For episodes of excessive or smelly intestinal gas, the use of a food diary may help identify the offending items. The author concludes by reiterating the importance of adequate fiber and fluid intake. The websites of four information resource organizations are listed. •

Constipation, Part I: The Hard Facts Source: Harvard Health Letter. 16(4): 1-4. February 1991. Summary: This article presents a general introduction to the most common gastrointestinal complaint in the United State, constipation. The author delineates five main categories of constipation, discusses possible causes of constipation, explains the typical diagnostic tests used, and reviews some of the basic facts of the biological processes of digestion and excretion. The author also briefly mentions the role of psychological factors in constipation. 1 figure.

•

Clinical Management of Intractable Constipation Source: Annals of Internal Medicine. 121(7): 520-528. October 1994. Summary: This article presents a review of the current management of intractable constipation. The authors identified by MEDLINE search original articles and reviews published in the English-language literature between 1965 and 1993. Key words included constipation, epidemiology, colonic inertia, pseudo-obstruction, pelvic floor dysfunction, and results of therapeutic interventions, particularly the effects of biofeedback training and subtotal colectomy. The authors conclude that, in most patients, constipation is usually due to lack of dietary fiber and responds to simple measures to correct these factors, often without need to consult a physician. In some, probably fewer than 10 percent of patients who consult their physicians, structural diseases of the colon and rectum, systemic disease, or medications that slow gut transit should be excluded, and regular exercise, dietary fiber, and an osmotic laxative prescribed. They present an algorithmic approach that can carefully select patients with intractable constipation for behavioral modification and biofeedback. The long-term outcome is excellent, with at least 75 percent success in several series. 2 figures. 2 tables. 73 references. (AA-M).

•

Pediatric Constipation Source: Gastroenterology Nursing. 19(3): 88-95. May-June 1996. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (800) 638-6423 or (410) 528-8555. Summary: This article presents an overview of pediatric constipation. The author defines constipation from a medical and nursing point of view. Intestinal pathophysiology as well as etiological theories of pediatric constipation are reviewed. The author presents current research and describes clinical treatment and experience in this area. The author also suggests topics for patient education (for family members), including normal GI anatomy and physiology; suspected etiology and alterations in

Studies

17

physiology with constipation; variability of stool patterns and stool characteristics; proper positioning for stooling; dietary factors; and the potential harm of some laxatives and manual stimulation techniques. 2 figures. 1 table. 93 references. (AA-M). •

Colectomy for Slow-Transit Constipation: Preoperative Functional Evaluation Is Important but Not a Guarantee for a Successful Outcome Source: Diseases of the Colon and Rectum. 44(4): 577-580. April 2001. Contact: Available from Lippincott Williams and Wilkins. P.O. Box 1600, Hagerstown, MD 21741. (800) 638-3030 or (301) 223-2300. Fax (301) 223-2365. Summary: This article reports on a study designed to assess the results of preoperative functional evaluation of patients with severe slow transit constipation in relation to functional outcome. The study included 439 patients with chronic intractable constipation who were evaluated by marker studies. Of these patients, 21 underwent colectomy (removal of a portion of the colon) and ileorectal anastomosis (reconnection of the ileum portion of the small intestine to the rectum) for slow transit constipation. Mean colorectal transit time was 156 hours (normal time is usually less than 45 hours). Small bowel transit time was normal in 10 patients and delayed in 5 patients. Six patients were nonresponders. Morbidity (illness or complications) was 33 percent. Small bowel obstruction occurred in 6 patients; relaparotomy was done in 4 patients. Follow up varied from 14 to 153 months. After three months, defecation frequency was increased in all patients. mean stool frequency improved from one bowel movement per 5.9 days to 2.8 times per day. Sixteen patients felt improved after surgery. Seventeen patients continued to experience abdominal pain, and 13 still used laxatives and enemas. Satisfaction rate was 76 percent (16 patients). After one year, defecation frequency was back at the preoperative level in 5 patients. An ileostomy was created in two more patients because of incontinence and persistent diarrhea. Eleven patients (52 percent) still felt improved. A relation between small bowel function and functional results could not be demonstrated. The authors conclude that preoperative evaluation is important but not a guarantee for successful outcome. Colectomy remains an ultimate option for patients with disabling slow transit constipation, but patients should be informed that, despite an increased defecation frequency, abdominal symptoms might persist. Any common use of colectomy to treat constipation should be discouraged. 1 table. 16 references.

•

Electrorectogram in Chronic Constipation, Ulcerative Proctitis, Hirschsprung's Disease, and Neurogenic Rectum Source: Practical Gastroenterology. 20(12): 13-20. December 1996. Contact: Available from Shugar Publishing, Inc. 99B Main Street, Westhampton Beach, NY 11978. (631) 288-4404. Fax (631) 288-4435. E-Mail: [email protected]. Summary: This article reports on a study in which recordings of rectal electrical activity (electrorectography, or ERG) were made in 23 healthy volunteers, 22 patients with chronic constipation (CC), 11 patients with ulcerative proctitis, 14 patients with Hirschsprung's disease (HD), and 28 patients with neurogenic rectum (NR). Normal ERG was manifested as regular slow waves or pacesetter potentials (PPs), which had constant frequency. Pacesetter potentials were followed randomly by action potentials (APs), which were associated with a mild increase of rectal pressure. In CC, two ERG patterns were identified: bradyrectia in inertia constipation and tachyrectia in obstructive constipation. Ulcerative proctitis manifested with tachyrectia and HD with 'silent' ERG (no PPs or APs). In NR, ERG of patients with upper motor neuron lesions

18

Constipation

exhibited rectoarrhythmia (irregular PPs), and patients with lower motor neuron lesions showed silent ERG. No complications occurred. The author concludes that rectal motility seems to be controlled by PPs. Disorders of rectal electrical rhythm or 'dysrhythmia' may cause rectal dysmotility and defecation disorders. The electrorectogram is noninvasive and nonradiologic and can be used as an effective investigational tool in rectal disorders. 8 figures. 1 table. 43 references. (AA-M). •

Constipation in an Elderly Community: A Study of Prevalence and Potential Risk Factors Source: American Journal of Gastroenterology. 91(1): 19-25. January 1996. Summary: This article reports on a study of the prevalence of and potential risk factors for constipation in a representative elderly community, using symptom-based diagnostic criteria. An age-and gender-stratified random sample of 1,833 residents of Olmsted County, MN, aged 65 years and over, was mailed a valid self-report questionnaire; 1,375 responded (75 percent). The overall age-and gender-adjusted prevalence (per 100) of any constipation was 40.1; for functional constipation and outlet difficulty or delay, the prevalence was 24.4 and 20.5, respectively. Self-reported constipation did not reliably identify functional constipation or outlet delay. Nonsteroidal anti-inflammatory drugs and other medications were significant risk factors in subjects with functional constipation and outlet delay combined. 3 figures. 3 tables. 21 references. (AA-M).

•

Cisapride for the Treatment of Constipation in Children: A Double-Blind Study Source: Journal of Pediatrics. 136(1): 35-40. January 2000. Contact: Available from Mosby, Inc. 11830 Westline Industrial Drive, St. Louis, MO 63146-3318. (800) 453-4351 or (314) 453-4351. Fax (314) 432-1158. Website: www.mosby.com. Summary: This article reports on a study undertaken to determine whether cisapride is effective in treating children with constipation. The double blind, placebo controlled study included children with chronic constipation who were randomly assigned to treatment with cisapride or placebo for 12 weeks. Forty children were enrolled, and 36 completed the therapy. Treatment successes occurred in 13 of 17 subjects in the cisapride group (76 percent) and 8 of 19 subjects in the placebo group (37 percent). The odds ratio for response after cisapride administration was 8.2 times higher. During cisapride therapy, there was a significant improvement in the number of spontaneous bowel movements per week and a significant decrease in the number of fecal soiling episodes per day, percentage with encopresis, number of laxative doses per week, percentage using laxatives, and total gastrointestinal transit time. With placebo, there were no significant changes in the number of spontaneous bowel movements, percentage with encopresis, or total gastrointestinal time; but there was a significant decrease in the number of fecal soiling episodes per day and the number of laxative doses per week. The authors conclude that cisapride was effective in treating children with constipation. The authors note, however, that cisapride is not recommended as the first line drug for children with constipation. Dietary fiber and other behavior changes are recommended first. 1 figure. 2 tables. 27 references.

•

Chronic Constipation in Children: Rational Management Source: Consultant. 42(12): 1723-1732. November 2001.

Studies

19

Contact: Available from Cliggott Publishing Company. 55 Holly Hill Lane, Box 4010, Greenwich, CT 06831-0010. Summary: This article reviews a strategy of rational management of chronic constipation in children. The authors note that irregular bowel habits are a common cause of chronic constipation in children; illness and travel are among the disruptions in daily routine that can result in stool withholding. Medical conditions, such as diabetes and Hirschsprung disease, and medications, including methylphenidate, analgesics, and cough syrups, can also cause constipation. Encopresis (fecal incontinence, or involuntary loss of stool), anal outlet bleeding, and rectal pain caused by anal fissures are associated with chronic constipation; hemorrhoids rarely develop in children. Barium enemas, survey films, and colonic transit studies can detect and define functional or structural obstruction. Physicians should recommend regular postprandial (after a meal) toilet visits; moderate exercise; and increased fluid and fiber intake, using a 'medicinal' fiber product if necessary. Parents should be discouraged from excessive use of laxatives and cathartics. Options for long term therapy include mineral oil and osmotic laxatives. 3 tables. 69 references. •

Medication-Induced Colonic Disease, Radiation Proctitis, Colonic Metabolism, and the Treatment of Diarrhea and Constipation Source: Current Opinion in Gastroenterology. 8: 57-62. February 1992. Summary: This article reviews large intestine-related recent articles on several topics, including medication-induced colonic disease, radiation proctitis, colonic metabolism, and the treatment of diarrhea and constipation. Medication-induced diseases discussed include injury from detergent enemas, analgesic suppositories containing acetylsalicylic acid and paracetamol, injury from nonsteroidal anti-inflammatory drugs, and colonic pseudoobstruction due to oral amphetamines. Articles dealing with radiation proctitis include a review of long-term complications, an animal model of proctitis cystica profunda, and treatment of chronic bleeding with hyperbaric oxygen. Studies of the role of short-chain fatty acids in colonic blood flow and on the treatment of chronic constipation with sorbitol are also reviewed. 3 figures. 26 annotated references. (AA-M).

•

Slow Transit Constipation Source: Gastroenterology Clinics of North America. 30(1): 77-95. March 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: This article reviews slow transit constipation, a clinical syndrome characterized by intractable constipation poorly responsive to dietary fiber and laxatives. Other gastrointestinal manifestations include abdominal pain, bloating, malaise, nausea, anorectal symptoms suggestive of difficult fecal expulsion, and delayed colonic transit without megacolon. Extragastrointestinal symptoms in this syndrome include painful or irregular menses, hesitancy in initiating micturition (urination), and somatic symptoms such as cold hands or blackout. The authors briefly discuss terminology and stress that slow transit constipation is the term used to define a disorder of colonic motor function, and is generally used for patients with delayed colonic transit but no underlying systemic disorder or pelvic floor dysfunction that explains their symptoms. The authors discuss epidemiology, pathophysiology, histology, clinical features, differential diagnosis, radiopaque marker diagnostic methods, scintigraphic techniques, medical treatments, surgical treatment, and the special situation of colonic dysfunction after spinal cord injury. The authors note that

20

Constipation

the disorder spans a spectrum of variable severity, ranging from patients who have relatively mild delays in transit but who are otherwise indistinguishable from irritable bowel syndrome patients at one extreme, to patients with colonic inertia or chronic megacolon at the other extreme. Potential mechanisms for impaired colonic propulsion include fewer colonic HAPCs (high amplitude propagated contractions) or a reduced colonic contractile response to a meal. The treatment is primarily medical; surgery is reserved for patients with severe disease or colonic inertia. 3 figures. 1 table. 85 references. •

Childhood Constipation: Evaluation and Treatment Source: Journal of Clinical Gastroenterology. 33(3): 199-205. 2001. Contact: Available from Lippincott Williams and Wilkins, Inc. 12107 Insurance Way, Hagerstown, MD 21740. (800) 638-3030 or (301) 714-2300. Summary: This article reviews the evaluation and treatment of childhood constipation, a common condition. The authors estimate that between 5 and 10 percent of pediatric patients have constipation or encopresis (fecal soiling). Constipation is the second most referred condition in pediatric gastroenterology practices, accounting for up to 25 percent of all visits. The authors lay out a practical approach for those physicians not familiar with constipation in children. The diagnosis of constipation requires careful history taking and interpretation. Diagnostic tests are not often needed and are reserved for those who are severely affected. The daily bowel habits of children are extremely susceptible to any changes in routine environment. Constipation and subsequent fecal retention behavior often begins soon after a child has experienced a painful evacuation. Childhood constipation can be difficult to treat and often requires prolonged support by physicians and parents, explanation, medical treatment, and most importantly, the child's cooperation. 1 figure. 5 tables. 31 references.

•

Preventing Constipation in Older People Source: Professional Nurse. 11(12): 816-819. September 1996. Contact: Available from Macmillan Magazines, Ltd. Porters South, Crinan Street, London N1 9XW, England. 0171-833-4000. Fax 0171-843-4699. Summary: This article reviews the problem of constipation in older people in hospitals and nursing homes and describes the nurse's role in preventing and treating the problem. Topics include research into bowel emptying, the causes of constipation, and prevention and treatment. Although diet, fluid intake, medication, and mobility can resolve this problem, laxative misuse is widespread. Nurses rarely consider bowel management as a central part of their role. However, by working with older people to restore normal bowel habits, nurses can help reduce laxative use and abuse, improve the health and well being of patients, and reduce nursing workload. 1 table. 22 references. (AA-M).

•

Biofeedback Training in Children with Functional Constipation: A Critical Review Source: Digestive Diseases and Sciences. 41(1): 65-71. January 1996. Summary: This article reviews the use of biofeedback training in children with functional constipation. Many uncontrolled studies suggest that biofeedback training is an effective adjunctive therapy in improving the outcome of functional constipation and/or encopresis in children. This could not be confirmed in controlled studies. Adding biofeedback training after conventional treatment had failed did not provide

Studies

21

benefits. The author concludes that the results of biofeedback treatment in children with functional constipation and/or encopresis are disappointing. 1 figure. 2 tables. 31 references. (AA-M). •

Basics of Constipation Source: Gastroenterology Nursing. 20(4): 125-128. July-August 1997. Contact: Available from Williams and Wilkins. 351 West Camden Street, Baltimore, MD 21201-2436. (410) 528-8555. Summary: This continuing education article updates gastroenterology nurses on the physiology and etiology of constipation. The author defines and describes the causes of constipation, reviews the physiology of the colon, and outlines the nurse's role in helping patients with constipation. Constipation is clinically defined as fewer than three bowel movements per week, which may also imply that stools are too small, too infrequent, hard in nature, difficult to expel, or that the individual has a feeling of incomplete evacuation after defecation. Extrinsic factors such as decreased activity, lack of privacy or time for defecation, dietary habits (e.g., low fiber intake), and a lack of fluids by mouth can result in primary constipation. Pharmacologic agents can alter colonic motility. The author stresses that constipation is usually the result of combined causes rather than a single factor. The nursing assessment of the patient should gather information about the patient's personal beliefs regarding elimination practices, what is viewed as a normal pattern, laxative use, diet, oral fluid intake, exercise habits, sleep patterns, recent illnesses, treatments, and present medications. Especially in elderly patients, the family may be a vital link to patient education. If the family can understand some of the combined causes of constipation, they are in a prime position to provide emotional, physical, and financial support to the patient. Instructions for a high fiber diet, increased fluid intake, laxative use, and exercise guidance tailored for age and mental and physical levels of ability need to be addressed with the patient and family. 3 tables. 9 references. (AA-M).

•

What You Can Do to Prevent and Treat Constipation Source: Guide to Women's Health. 12, 14. April 2001. Contact: Available from Springhouse Corporation. 1111 Bethlehem Pike, P.O. Box 908, Springhouse, PA 19477. (215) 646-8700. Fax (215) 540-0668. Summary: This fact sheet reviews strategies that readers can follow to prevent and treat constipation. Most cases of constipation are temporary and not serious. Poor diet and lack of exercise are usually to blame, and in most cases, simple dietary and lifestyle changes will relieve symptoms and help prevent constipation from recurring. A diet with enough fiber (20 to 35 grams each day) helps form soft, bulky stool. Good sources of fiber include beans, whole grains and bran cereals, fresh fruits, and vegetables such as asparagus, brussels sprouts, cabbage, and carrots. Other changes that can help treat and prevent constipation include: drinking enough water and other liquids; engaging in daily exercise; reserving enough time to have a bowel movement; and not ignoring the urge to have a bowel movement. Health care providers may recommend laxatives or enemas for a limited time in patients who have a slow response to these lifestyle changes. The fact sheet outlines different types of laxatives, including bulk forming laxatives, stimulants, stool softeners, and saline laxatives. For chronic constipation or constipation caused by problems such as rectal prolapse, anorectal dysfunction, or colonic inertia, surgical options may be recommended by the health care provider. One sidebar lists the common causes of constipation.

22

Constipation

•

Constipation: Common-Sense Care of the Older Patient Source: Geriatrics. 51(12): 28-32, 34, 36. December 1996. Summary: This gerontology article discusses constipation, a common complaint in older patients. Contributing factors are impaired general health, use of medications, and decreased mobility and physical activity. The authors note that diet has an indeterminate effect. Many patients become gradually more constipated with age and self-treat with over-the-counter laxatives. Investigation is warranted if defecation is associated with pain or bloating, or if it represents a recent change in bowel habit. Although constipation is usually just an annoyance, it can have more serious consequences, such as impaction and ulceration. A combination of bowel training, dietary management, and regular exercise is the first phase of treatment. Bulk laxatives are recommended as second-line treatment, followed by other laxatives if needed. The authors also recommend that, once a good regimen is achieved, dosages of laxatives should be reduced to the minimally effective range, particularly if laxatives with potentially dangerous side effects are used. Indeed, lifestyle changes alone (bowel training, exercise, and diet) may ultimately be adequate therapy for most older patients suffering from this common condition. 1 figure. 2 tables. 20 references. (AA-M).

•

Surgical Treatment of Constipation and Fecal Incontinence Source: Gastroenterology Clinics of North America. 30(1): 131-166. March 2001. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 32821-9816. (800) 654-2452. Summary: This lengthy article reviews the surgical treatment of constipation and fecal incontinence. The authors emphasize that success in the management of constipation depends on an accurate determination of the cause. Because there are many extracolonic causes that can produce constipation, a detailed clinical history should be taken. Before physiologic investigation, patients must discontinue the use of medications that may cause or exacerbate their symptoms. A proper diet should be maintained, and patients must be supervised by a dietitian or a physician for a minimum of 3 to 6 months before any extensive physiologic evaluation is undertaken and before any surgery is considered. Diagnostic tests may include anorectal examination, colonic transit study, proctography and cinedefecography, electromyography, manometry, small bowel transit study, Minnesota Multiphasic Personality Inventory, and rectal biopsy. Surgery for constipation is reserved for a highly select group of patients; the authors review the indications for patients with pelvic outlet obstruction, with colonic inertia (slow transit throughout the colon), and with combined outlet obstruction and colonic inertia. The authors then discuss fecal incontinence, noting that obstetric injury (during childbirth) is a major cause and one amenable to surgical correction. Diagnostic tests can include physical examination, manometry, electromyography, pudendal nerve terminal motor latency, anal ultrasonography, and magnetic resonance imaging (MRI). The treatment of fecal incontinence should always be directed to the cause; many individuals can be managed adequately by noninvasive means. Surgical treatment can include sphincter repair, muscle transplant, the use of synthetic material, and diversion (the creation of a stoma). 4 figures. 9 tables. 297 references.

•

Anorectal and Pelvic Floor Function: Relevance to Continence, Incontinence, and Constipation Source: Gastroenterology Clinics of North America. 25(1): 163-182. March 1996.

Studies

23

Contact: Available from W.B. Saunders Company. Periodicals Fulfillment, 6277 Sea Harbor Drive, Orlando, FL 32887. (800) 654-2452. Summary: This review article discusses anorectal and pelvic floor function; its relevance to continence, incontinence, and constipation; and tests that assess said function. The authors note that diagnostic tests are most useful when they identify anatomic or physiologic abnormalities for which there are successful treatments. For the incontinent patient, anal manometry is the most useful test. Sphincter injuries should be repaired, whereas neurogenic incontinence is best treated initially with biofeedback. Three tests are most useful for the constipated patients: colonic transit time; degree of pelvic floor descent on straining; and balloon expulsion. Colonic inertia responds to total colectomy and pelvic floor dysfunction to biofeedback. Meanwhile, patients found to have irritable bowel syndrome (IBS) need to be re-referred to their physicians. 4 figures. 2 tables. 102 references. (AA-M). •

AGA Technical Review on Constipation Source: Gastroenterology. 119(6): 1766-1778. December 2000. Contact: Available from W.B. Saunders Company. 6277 Sea Harbor Drive, Orlando, FL 19106-3399. (800) 654-2452 or (407) 345-4000. Summary: This technical review identifies a rational, effective, and cost effective approach to the patient presenting with constipation. The authors review the epidemiology of constipation, risk factors, the economic impact of constipation, the clinical features and pathophysiology, clinical evaluation, secondary encounters and referral consultations, diagnostic tests (balloon expulsion test, defecography, colonic transit, and anorectal manometry), medical management, and the role of surgery in treating constipation. Constipation is associated with inactivity, low caloric intake, the number of medications being taken, low income, and a low education level. Constipation is also associated with depression as well as with physical and sexual abuse. These are noted as risk factors, not necessarily as causative agents. The review summarizes three patient care algorithms. After the initial history and physical examination, patients can be classified into one of several subgroups. Standard blood tests and a colonic structural evaluation should be performed to rule out organic causes of the constipation. If the initial evaluation is normal or negative, an empiric trial of fiber (and or dietary changes) can be followed by simple osmotic laxatives. Most patients will obtain symptom relief with these measures. Patients who fail to respond to this initial approach are appropriate candidates for more specialized testing. 5 tables. 95 references.

Federally Funded Research on Constipation The U.S. Government supports a variety of research studies relating to constipation. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions.

2

Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

24

Constipation

Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to constipation. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore constipation. The following is typical of the type of information found when searching the CRISP database for constipation: •

Project Title: OUTCOMES

A

CAREGIVER

INTERVENTION

TO

IMPROVE

HOSPICE

Principal Investigator & Institution: Mcmillan, Susan C.; Professor; None; University of South Florida 4202 E Fowler Ave Tampa, Fl 33620 Timing: Fiscal Year 2001; Project Start 01-SEP-1999; Project End 30-JUN-2003 Summary: Although hospice family caregivers receive support from the hospice team, research indicates that a greater level of support and education are needed to assist them with the enormous responsibility they bear for physical and emotional care. If the caregiver is not adequately prepared to assess patients and provide needed care, the patient's quality of life may suffer, and the caregiver may experience feelings of inadequacy, anxiety, and depression leading to decreased caregiver quality of life. The primary aim of this experimental study, based on the stress-process model, is to improve the quality of life of hospice caregivers by helping them to master the skills needed to better assess and manage specific problems experienced by cancer patients (pain, dyspnea, constipation), thus enhancing caregiver coping and self-appraisal of stressfulness of patient symptoms and quality of life for both patients and caregivers. The sample of 480 patient/caregiver dyads will be drawn from a large hospice in the local area and screened using measures of functional status and mental status. After consenting, subjects will be randomly divided into three groups, a control group receiving standard care (Group I), a group receiving standard care plus friendly visits (Group II), and a group receiving standard care plus the intervention (Group III). The intervention will be based on the COPE method (Creativity, Optimism, Planning, Expert Information). Groups II and III will receive visits on the same schedule to control for the effects of researcher time and attention. On visit one, caregivers in Group III will be taught to use the COPE method of managing patient problems. Visit one will last approximately 90 minutes; visits two and three will reinforce and extend learning and last approximately 30 minutes each. Group III caregivers will receive a copy of the Home Care Guide for Advanced Cancer and receive two supportive telephone calls from the RA-intervention nurse, one after visit one and one after visit two. Group III caregivers will be taught how to assess patient symptom intensity and given a preformatted diary in which to record symptom intensity scores twice daily. Data will be collected from patients about symptom intensity, symptom distress, and quality of life. Caregiver data will include coping, self-appraisal, and quality of life including mastery. Data will be collected from all three groups on admission to the study, immediately post intervention (day 16), and four weeks after admission to the study (day 30). One year after admission to hospice, all caregivers again will be contacted for data collection (patients are expected to be deceased). Quantitative data will be analyzed using repeated measures multivariate analysis of variance and structural equation modeling. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

25

Project Title: BIOFEEDBACK FOR FECAL INCONTINENCE AND CONSTIPATION Principal Investigator & Institution: Whitehead, William E.; Professor of Medicine; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 30-NOV-2004 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: BLADDER AND BOWEL CONTROL USING NEUROPROSTHETIC DEVICES Principal Investigator & Institution: Creasy, Graham; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2001 Summary: Electrical stimulators resembling pacemakers were designed to improve bladder emptying following spinal cord injury, by stimulating the nerve roots at the base of the spine. This causes contraction of the bladder and has been shown in about 90% of the patients on whom it has been used to improve bladder emptying and reduce urine infection. It can also improve continence. This project will document these results accurately in the United States. The stimulator also causes contraction of the rectum and most of the patients in whom it has been used report a reduction in constipation. Techniques for more selective stimulation of the bladder and bowel have been developed by the investigators at CWRU. This project provides an opportunity for evaluating the functional benefit to be gained in human subjects for these techniques. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: CONTRACTILE SIGNAL TRANSDUCTION IN ULCERATIVE COLITIS Principal Investigator & Institution: Cao, Weibiao; Rhode Island Hospital (Providence, Ri) Providence, Ri 02903 Timing: Fiscal Year 2003; Project Start 10-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Ulcerative colitis is a chronic inflammatory condition affecting the large bowel: Although it is most frequent in the rectosigrnoid area, it may involve the whole colon. Inflammation in ulcerative colitis is histologically limited to the mucosa, and its effects have been better characterized in the superficial than in the deeper layers such as muscularis propria. Inflammation, however, may affect the muscle layer, leading to motor dysfunction, which contributes to key clinical symptoms, including diarrhea, constipation, and crampy abdominal pain. To define inflammation, associated changes in motor function we will examine the circular muscle from the sigmoid colon from patient with active ulcerative colitis and compare it with muscle from disease-free margins of histologically normal colon tissue from cancer resections. The sigmoid is most often involved and frequently resected, and this avoids variations associated with different anatomical locations of the disease. In preliminary experiments, we find that inflammatory mediators such as interleukin-1beta and hydrogen peroxide are present in the muscularis propria. Our central hypothesis is that inflammatory mediators, first produced by inflammatory cells in the mucosa, may induce production of additional mediators by the target cells themselves, and that in time the muscularis propria becomes affected leading to motor disturbances. We therefore propose to: A) Define inflammation-induced changes in contractile signal

26

Constipation

transduction pathways of human sigmoid colon. B) Test the effect of selected inflammatory mediators, known to be present in ulcerative colitis mucosa, to determine their individual contribution to the observed changes in colonic motor function. C) Determine whether inhibition of selected inflammatory mediators may reverse inflammation-mediated changes in colonic motor function. Examining the relationship between inflammatory mechanisms and changes in motor function may help in understanding the functional disturbances associated with ulcerative colitis and identifying new targets for therapeutic intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CONTROL OF RECTOANAL MOTILITY Principal Investigator & Institution: Keef, Kathleen D.; Professor; Physiology and Cell Biology; University of Nevada Reno Reno, Nv 89557 Timing: Fiscal Year 2001; Project Start 15-AUG-2000; Project End 31-JUL-2004 Summary: The rectoanal region of the GI tract regulates the final storage, transport and evacuation of the GI contents. These functions require substantial differences in the contractile behavior of progressively more distal segments of this region. This study investigates the mechanisms underlying spontaneous motility patterns and the actions of excitatory nerves in rectoanal circular muscle of the dog and mouse gastrointestinal tract. The overall hypothesis for these studies is that fundamental changes occur in the nature of pacemaker activity, neuronal innervation and the actions of norepinephrine (NE) and acetylcholine (ACh) which permit adjacent portions of the rectoanal region to perform complimentary but distinct functions. Membrane potential and contractile activity will be measured as well as receptor density using radioligand binding techniques. These data will be compared to immunohistochemical and immunocytochemical measurements to identify putative pacemaker cells (i.e., interstitial cells of Cajal or ICC) and their relationship to intrinsic and extrinsic nerves. An 8 cm region of the canine model and a 1 cm region of the mouse model encompassing both the rectum and internal anal sphincter (IAS) will be used. The specific aims of this proposal are: 1) To compare the spatial distribution of pacemaker potentials to ICC, 2) To characterize the changes which occur in functional motor innervation with distance in the rectoanal region, 3) To determine the anatomical distribution of nerves and their relationship to the distribution of ICC, 4) To evaluate postjunctional adrenergic and muscarinic responses in the rectoanal region using functional measurements and radioligand binding techniques, 5) To evaluate pacemaking using knockout mice and organ culture techniques. Millions of Americans suffer from diseases of the rectoanal region which lead to either constipation or fecal incontinence. The experiments outlined in this proposal will provide important new information regarding the anatomical and physiological characteristics which underlie rectoanal motility and its nervous control. In so doing we may aid future studies directed toward understanding how these functions become altered in disease states. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: DEVELOPMEMT OF NOVEL TREATMENTS FOR NICOTINE ADDICTION Principal Investigator & Institution: Dwoskin, Linda P.; Professor; Pharmaceutical Sciences; University of Kentucky 109 Kinkead Hall Lexington, Ky 40506 Timing: Fiscal Year 2003; Project Start 30-SEP-2003; Project End 30-JUN-2008

Studies

27

Summary: (provided by applicant): Tobacco smoking is the number one health problem accounting for more illnesses and deaths in the US than any other factor. Despite efficacy of some current pharmacotherapies (i.e., nicotine replacement and bupropion), relapse rates continue to be high, indicating that novel medications are needed. Research in the current application proposes to develop a new class of subtype-selective nicotinic receptor (nAChR) antagonists as therapeutic agents with efficacy for tobacco use cessation and for treatment of nicotine dependence. As much as tobacco use behavior and nicotine addiction have links to depression, these novel drug candidates may also prove to be new treatments for depression. Based on the observations that the bupropion acts as a nAChR antagonist and that the nonselective nAChR antagonist, mecamylamine, has some efficacy as a tobacco use cessation agent, but is limited by its peripherally-mediated side-effect of constipation, we predict that the subtype-selective nAChR antagonists, which we propose to develop, may have therapeutic advantages and efficacy as tobacco use cessation agents in the treatment of nicotine addiction. We hypothesize that quaternizing the pyridine-N atom of the nicotine molecule with a lipophillic N-substituent to afford N-nicotinium analogs and/or by connecting these quaternary ammonium moieties with a lipophillic linker to afford N,N'-bis-analogs will result in subtype-selective nAChR antagonists, which will inhibit either nicotine-evoked dopamine, norepinephrine or serotonin release, and thus, inhibit nicotineinduced behaviors, indicating their potential as nicotine addiction treatments. Brain bioavailability, pharmacokinetics and metabolism of the lead candidates will also be evaluated. Comparison of results using native and recombinant nAChRs will provide new insights into the subunit composition of nAChRs mediating these functions. Drug candidates will be assessed for their ability to decrease nicotine self-administration, to decrease nicotine-induced reinstatement of nicotine seeking behavior, and to precipitate withdrawal in nicotine-dependent animals. Thus, an integrative approach (i.e., medicinal chemistry, pharmacokinetics, metabolism, pharmacology, psychology and neuroscience) will be used to increase our understanding of the underlying mechanisms of tobacco use and nicotine addiction, with focus on pharmacotherapeutic candidate development. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DISCOVERY OF K OPIOID ANALGESICS USING CHIMERIC RECEPTOR Principal Investigator & Institution: Dehaven, Robert N.; Adolor Corporation 371 Phoenixville Pike Malvern, Pa 19355 Timing: Fiscal Year 2001; Project Start 01-SEP-2001; Project End 28-FEB-2002 Summary: (provided by applicant): Pain is a serious, debilitating condition that is under treated because of the dose limiting side effects of currently used opiate therapeutics including respiratory depression, constipation, nausea, and physical dependence at therapeutic doses. Although arylacetamide K opioid agonists do not cause these side effects, they produce visual hallucinations and dysphoria. The endogenous agonist of the K opioid receptor, dynorphin A, and a stable peptide analog, E2078, produce analgesia in humans without causing dysphoria. The arylacetamides and dynorphins bind to different domains of the K receptor, which may result in the different in vivo pharmacological and clinically meaningful side effect profiles observed for these structurally diverse molecules. We propose to develop novel K receptor agonists that do not cause dysphoria by using differential binding to a chimeric receptor as a highthroughput screening tool. Compounds that bind to the K receptor in the same manner as dynorphin A and E2078 will then be tested in animals to determine whether they

28

Constipation

induce analgesia without causing the dysphoric side effects of previously developed arylacetamides that have been tested in man. Compounds that possess the desired pharmacological profile will be rapidly advanced into preclinical and clinical development. PROPOSED COMMERCIAL APPLICATION: Chronic pain. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FUNCTION OF THE ENTERIC NERVOUS SYSTEM Principal Investigator & Institution: Wood, Jackie D.; Professor and Chairman; Physiology and Cell Biology; Ohio State University 1800 Cannon Dr, Rm 1210 Columbus, Oh 43210 Timing: Fiscal Year 2003; Project Start 01-SEP-1985; Project End 30-JUN-2008 Summary: (provided by applicant): This 5-year project of research on the enteric nervous system is designed to improve understanding of the cellular and molecular neurophysiology of secretomotor neurons in the intestinal submucosal plexus and inhibitory and excitatory motor neurons in the myenteric plexus that innervate the intestinal musculature. Cellular neurophysiology underlies functions of secretomotor neurons that are basic to control of fluidity of the intestinal contents in states of health and to diarrhea and constipation in disordered states. Cellular neurophysiology of musculomotor neurons is basic to control of muscular contraction in normal motility and disordered motility in disease states. Aims of the project are based on pilot/feasibility results, which suggest that slow excitatory neurotransmission in enteric motor neurons is specialized and different from this form of synaptic transmission in other kinds of enteric neurons. The pilot/feasibility data for secretomotor and musculomotor neurons suggest that this class of neurons express in common the properties of uniaxonal morphology, S-type electrophysiological behavior, increased ionic conductance during slow excitatory neurotransmission, and a metabotropic signal transduction cascade that involves calmodulin kinases and protein kinase C, but not cAMP and protein kinase A. The project has five specific aims. Aim 1 is organized to test the hypothesis that opening of non-selective cationic and perhaps chloride conductance channels accounts for the membrane depolarization seen during the slow EPSP in neurons identified morphologically and immunohistochemically as motor neurons in the myenteric and submucosal plexuses. Aim 2 tests the hypothesis that activation of phospholipase C, IP3 release and mobilization of intraneuronal calcium are steps in the signal transduction cascade for the newly recognized slow EPSP in enteric motor neurons. Aim 3 tests the hypothesis that calcium binding to calmodulin is a key step in the signaling mechanisms that underlie the specialized slow EPSP. Aim 4 tests the expectation that calmodulin kinases II & IV and activation of protein kinase C are steps in the calcium signaling cascade for the EPSP. Aim 5 tests suggestions that activation of protein kinase C by calmodulin kinases leads to phorphorylation and opening of the ionic channels that underlie depolarization of the membrane potential and enhanced excitability that occurs during slow synaptic excitation in enteric motor neurons. Dephosphorylation of the channels by the phosphatase, calcineurin, terminates slow EPSP. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: GASTROINTESTINAL SMOOTH MUSCLE IN HEALTH AND DISEASE Principal Investigator & Institution: Szurszewski, Joseph H.; Professor and Chair; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905

Studies

29

Timing: Fiscal Year 2001; Project Start 01-DEC-1976; Project End 31-JAN-2002 Summary: The long term objective is to provide a quantitative understanding of the myogenic and neurogenic processes which regulate gastrointestinal smooth muscle activity in experimental animals and in man. Smooth muscle from the internal anal sphincter, ileocolonic/ileocecal sphincter, muscularis mucosa of the esophagus, small and large intestines and the inner and outer circular muscle lamellae will be used. The areas of particular interest are: (1) the electrophysiological properties of the smooth muscle cell membrane in each of these areas; (2) the electrophysiological characteristics of neuroeffector responses; (3) the pattern of intramural innervation; (4) the identity of the neurotransmitters which cause excitation and inhibition; and (5) the electrophysiological and neurotransmission processes in normal and diseased human GI smooth muscle. The methods of approach will involve recording simultaneously mechanical and intracellular electrical activity, the recording of contractility of strips of muscle, radio-immunoassay of muscle to identify the type and content of peptides and radio-immunological and immunological techniques to identify the excitatory and inhibitiory transmitters. In vitro studies are planned. Dogs, cats, rabbits, guinea pigs and human GI smooth muscle will be used. These studies may be particularly relevant to understanding motor disturbances involving hypoganglionosis of the intrinsic plexuses in man. They man also be relevant to disturbances in anal continence in man. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC STUDY OF C ELEGANS HOST RESPONSE TO A PATHOGEN Principal Investigator & Institution: Yook, Karen J.; University of Oxford University Office, Wellington Sq Oxford, Timing: Fiscal Year 2001; Project Start 27-JAN-2001 Summary: elegans is well characterized and is amenable to forward genetic analysis and molecular dissection. Thus, worm genes that are required for the bacterial infection to proceed can be mutated and studied. Mutations in these genes will confer resistance to M. nematophilum infection. For example, mutations in genes required for the proper expression of extracellular proteins on the cuticle of the worm, confer resistance to the bacteria. This suggests that the bacteria (provided by applicant): How does an animal respond to a bacterial infection? Caenorhabditis elegans is a free-living soil nematode that can be infected by the bacterium Microbacterium nematophilum. Unlike other bacterial pathogens of C. elegans, M nematophilum does not kill the worm, rather, the bacteria adheres to the tail of the worm causing constipation and a distinct deformed anal region phenotype. Therefore, this interaction is reminiscent of a chronic disease state rather than a general toxicity response. Although M nematophilum is in the poorly characterized coryneform family of bacteria, C. rely on these cuticle factors during pathogenesis. In addition, 11 other bacterial resistance-conferring mutations termed bus for bacterial unswollen were mapped in the Hodgkin laboratory. These genes remain to be characterized. Alternatively, worm genes used to defend against the bacterial pathogen can be mutated and studied. Mutations in these genes will confer hypersensitivity to M. nematophilum infection. Screens for these genes uncovered three mutations that fall into two classes, gmp (growth impaired by M nematophilum pathogen) and emp (excess deformation by M nematophilum pathogen). These genes also remain to be cloned and characterized. Thus characterization of mutations that alters the host response to this pathogen should not only uncover the molecular pathways required for a bacterial infection process but also the molecular pathways used by the host to fight infection. To fully understand how C. elegans responds to M

30

Constipation

nematophilum, the bacterial resistance and hypersensitive screens will be saturated to find all of the genes involved in this process. In addition the genes already isolated will be cloned and characterized. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GRADUAL EXPOSURE TREATMENT FOR IRRITABLE BOWEL SYNDROME Principal Investigator & Institution: Decola, Joseph P.; Psychology; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2001; Project Start 01-APR-2001 Summary: The most commonly used non-medical treatment for Irritable Bowel Syndrome (IBS) is a combination of traditional stress management techniques and nonspecific cognitive therapy methods. This general approach is used to treat patients with divergent target symptoms (i.e., constipation and diarrhea). A limitation of this approach is that the treatment is not derived from a clear theoretical model that identifies a specific process underlying the disorder or treatment. The present study is based on a strong theoretical model that offers specific predictions and treatment methods. The model assumes that hypervigilance and hypersensitivity to internal sensations in the gut are the critical perceptual mechanisms underlying IBS. These perceptual filters are the result of learning and conditioning processes and can be reversed with a cognitive-behavioral treatment that incorporates gradual exposure to internal sensations. Subject recruitment will be limited to IBS patients with diarrhea as the predominant symptom and the treatment will be implemented with a multiple baseline across subject design. The treatment will consist of several phases: education about the role of learning in the development of IBS symptoms; relaxation training; cognitive restructuring for overestimation and catastrophization errors; exposure to the feared internal sensations; and exposure to avoided situations. The goal of this treatment is to reverse the hypersensitivity and hyperviligance through gradual exposure to these stimuli. The broad objective of this research is to enhance the treatment for IBS and to test the predictions of this theoretical model. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: IDENTIFICATION & ANALYSES OF THE UROFACIAL SYNDROME GENE Principal Investigator & Institution: She, Jin-Xiong; Professor and Director; Pathology, Immunol & Lab Med; University of Florida Gainesville, Fl 32611 Timing: Fiscal Year 2001; Project Start 01-JUN-1998; Project End 31-MAY-2003 Summary: (Adapted from the applicant's abstract) The Urofacial (Ochoa) syndrome (UFS, OMIM #236730) is an autosomal recessive disease characterized by congenital obstructive uropathy due to a neurogenic bladder, constipation and abnormal facial expression. Pedigree analysis has shown that a single gene is responsible for the syndrome. Because muscular function of multiple organs or tissues is involved (i.e., bladder, bowel and facial muscles), it is believed that the lesion may reside in the brain regions that coordinate muscle actions, such as micturition, defecation and facial muscle movement. Our recent genome screen has mapped the UFS gene to an interval of approximately 1cM (1Mb) between D10S184 and D10S603 on 10q23-q24. The goal of this proposal is to identify the disease gene using fine-mapping, positional candidate and positional cloning techniques. Three specific aims are proposed: 1. To further reduce the size of the genomic interval containing the UFS gene. Three complementary approaches

Studies

31

will be used to accomplish this aim. The first two approaches are based on linkage disequilibrium analyses and the third approach seeks to identify possible deletions/insertions of genomic DNA fragments involving the UFS gene. 2. To identify the UFS gene using positional candidate approach and/or positional cloning. Candidate genes in the UFS interval will be evaluated by identifying mutations and assessing their correlation with the occurrence of disease phenotype and carrier status. If candidate gene analyses fail to identify the UFS gene, additional coding sequences in the UFS interval will be identified using several positional cloning techniques including exon trapping, cDNA selection and genomic sequencing. 3. To characterize the structure, expression, regulatory elements, and function of the disease gene. The proposed studies should permit revelation of the gene responsible for UFS. Identification of the gene may provide important insight for a large number of voiding dysfunctions and other related neurologic uropathies that are major health problems in the US and the world. The gene may also be important for understanding the molecular basis and normal physiology of the coordination of muscle actions by the nervous system. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPROVING OF CARE BY REVERSAL OF OPIOID CONSTIPATION Principal Investigator & Institution: Yuan, Chun-Su; Anesthesia and Critical Care; University of Chicago 5801 S Ellis Ave Chicago, Il 60637 Timing: Fiscal Year 2001; Project Start 18-FEB-2000; Project End 31-JAN-2004 Summary: Morphine and other opioids are widely used analgesics in advanced cancer patients, and constipation is the most common treatment-associated side effect of opioid pain medications. Conventional measures for opioid-induced constipation are often insufficient, and constipation becomes a limiting factor in opioid use and opioid dose in these patients. A significant number of hospice patients receiving chronic opioids for pain would rather endure their pain than face the severe incapacitating constipation that opioids cause. Thus, opioid-induced constipation, a symptom secondary to the treatment, has a significant negative impact on the quality of life of these terminal patients. Palliative care and end of life management practices have received insufficient attention in the past, and the need to enhance palliative care of dying patients has become apparent in this country. In this proposed project, the efficacy of a novel peripheral opioid receptor antagonist, methylnaltrexone, in the treatment of chronic opioid-induced constipation, will be evaluated. Specific Aim 1 and 2 studies will utilize a clinical pharmacology approach (Phase II/III trials) to evaluate the efficacy and doseresponse of intravenous and oral methylnaltrexone in reversing chronic opioid-induced gut motility changes and constipation in methadone addicts and patients with advanced malignant conditions. These trials will be randomized, double-blind, placebocontrolled studies. In these studies, the oral-cecal transit time will be measured using the lactulose hydrogen breath test, and positive laxation response and opioid analgesic effect will be evaluated. In addition, subjective visual analog scale (VAS) scores for constipation, stool frequency and consistency, and "overall well being" will be recorded. Pharmacokinetic data will also be collected. In these studies, mechanisms underlying opioid gastrointestinal pharmacology in humans, an issue that has not been addressed before, will be investigated, since translation of data from previous animal experiments to humans may be problematic due to differences in the physiology of the opioid systems. Bringing methylnaltrexone, the first selective peripheral opioid receptor antagonist, to clinical application will be a significant advance in palliative care. Successful completion of this project will lead to a number of future studies in which

32

Constipation

other applications of methylnaltrexone, as well as its mechanisms of action of both opioids and their antagonism in humans, can be explored. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MULTICENTER TRIAL OF FUNCTIONAL BOWEL DISORDERS Principal Investigator & Institution: Drossman, Douglas Arnold.; Medicine; University of North Carolina Chapel Hill Office of Sponsored Research Chapel Hill, Nc 27599 Timing: Fiscal Year 2001; Project Start 30-SEP-1995; Project End 31-AUG-2003 Summary: The primary aim of this study is to compare the efficacies of clinical treatments for the group of chronic, painful functional bowel disorders (FBD) that predominantly affect women. Secondary aims include 1) determination of demographic, psychosocial, physiologic and symptomatic predictors of clinical improvement and 2) analysis of significant relationships among physiologic markers of FBD, psychosocial status, symptoms and treatment effects. The Principal Investigator and his colleagues propose to compare cognitive-behavioral psychological treatment with antidepressant drug therapy (desipramine) and education/attention placebo in over 300 women. Interrelationships between psychological and physiological factors on the development, clinical expression and treatment of FBD have long been recognized, but this is the first large-scale study designed both to isolate therapeutic effects, and to investigate interactions among physiologic measures, psychologic and sociodemographic factors, severity of symptoms, and therapeutic improvement including quality of life. In the proposed plan of research, at least 300 female patients (aged 18- 65) with FBD (irritable bowel syndrome, painful constipation and/or functional abdominal pain) will be enrolled in clinics at UNC-Chapel Hill and Toronto, Canada. A severity index will determine recruitment into the group of moderate FBD (200 patients) and severe FBD (100 patients). Each group will be randomized into the three treatment arms (cognitivebehavioral treatment, desipramine, and education/attention placebo), treated over a 12week period, and followed for one year. Outcome measures will include symptoms (standardized abdominal pain, stool form, and frequency) using diary cards, daily functional status (Sickness Impact Profile), depression (HAM-D), and psychological distress (SCL-90), physiological measures (enhanced rectal motility and visceralsensation), and health care use. Multivariate statistical methods with a hierarchical design will be applied to the data to assure maintenance of statistical power over multiple tests of overlapping groups. The results of this study may significantly improve an understanding of this complicated syndrome that lowers the quality of life and economic productivity of large numbers of women. The clinical impact of the study, in providing physicians with scientific evidence of the efficacy of treatments of FBD that are commonly used in practice, may be significant. This study may provide clinicians with predictors of success among types of FBD patients and types of therapy that will improve symptoms and quality of life and reduce the health care costs associated with this common syndrome, while improving patient-physician satisfaction. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NEUROCHEMISTRY OF NOCICEPTION Principal Investigator & Institution: Mantyh, Patrick W.; Professor; Polymer Science & Engineering; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2001; Project Start 01-AUG-1998; Project End 30-JUN-2003

Studies

33

Summary: (Applicant's Abstract) Management of chronic painful syndromes presents a tremendous challenge to the medical field as current pain management approaches with narcotics, such as morphine, carry adverse side effects such as sedation, constipation, tolerance and addiction. Therefore, a greater understanding of pathophysiological mechanisms that lead to a chronic pain state is needed for development of novel and effective therapies with minimal side effects. Recently, we demonstrated that when a conjugate of substance P (SP) and the ribosome-inactivating protein saporin (SAP) is infused into the spinal cord, the SP-SAP conjugate is specifically internalized and cytotoxic to lamina I spinal cord neurons that express the substance P receptor (SPR). This treatment leaves responses to mild noxious stimuli unchanged, but profoundly attenuates responses to highly noxious stimuli and to mechanical and thermal hyperalgesia. Using the intrathecal infusion of SP-SAP in the rat spinal cord as our model we propose: to investigate whether this treatment can alleviate inflammatory and/or neuropathic persistent pain states (Aim 1); to further define the rostral brain areas these neurons project to and the other receptors and neurotransmitters that are expressed by lamina I SPR-expressing neurons (Aim 2); to determine the functional role of neurons that express the SPR in nociceptive processing and hyperalgesia, and whether these SPR expressing neurons are functionally different from nociceptive neurons that do not express the SPR (Aim 3); and to determine whether reorganization of the spinal cord and dorsal root ganglia occurs following SP-SAP treatment and whether morphine is still effective in attenuating nociceptive responses (Aim 4). Information from these investigations will provide significant insight into the neurochemistry of spinal nociceptive signaling and whether SP-SAP treatment shows promise for developing non-opioid therapies to control chronic pain in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NEUROHUMORAL CONTROL OF INTERNAL ANAL SPHINCTER Principal Investigator & Institution: Rattan, Satish C.; Professor; Medicine; Thomas Jefferson University Office of Research Administration Philadelphia, Pa 191075587 Timing: Fiscal Year 2002; Project Start 01-JUL-1985; Project End 30-JUN-2006 Summary: (provided by applicant): Disorders of the internal anal sphincter (IAS) underlie many clinical abnormalities, such as fecal incontinence and constipation, and emphasize its role in continence and defecation. Disorders of the IAS occur more frequently in the rapidly expanding population of the elderly, and thus give increased urgency to understanding its function. Therefore, the objectives of this research proposal are: 1) to investigate intracellular mechanisms that regulate the basal tone of the LAS, and 2) to determine the role of cellular and biochemical elements in the nonadrenergic noncholinergic (NANC)-mediated relaxation of the IAS. Relations between electrical and mechanical activities will be determined by simultaneous recordings in IAS isolated from the external anal sphincter (EAS), in vivo and in vitro. Correlations between intracellular biochemistry and contraction-relaxation of the IAS will be obtained by measurements of changes in membrane potentials, flux in free intracellular Ca2turnover of Pt, G-proteins, activities of protein kinase C, myosin light chain kinase (MLCK) and MLC-phosphatase, and the state of phosphorylation of myosin light chain (MLC20-P). In addition, we will determine cyclic nucleotides, immunocytochemical localization, direct release of the mediators, and enzymatic activities involved in their biosynthesis. Murine models with targeted disruption of a specific gene which render them deficient in either intramuscular interstitial cells of Cajal (ICC-IM; WWV), nNOS (nNOS-/-), or HO-2 (HO-2-/-) will be used to determine cellular and biochemical elements which regulate the basal tone and the nature of inhibitory neurotransmission

34

Constipation

in the LAS. Either mice or opossums will be used in almost all of the above studies, as these are well-characterized animal models for the study of the LAS. Our multidisciplinary approach to the study of the IAS will define: (1) the cellular bases and signaling pathways most critical to the regulation of the LAS tone, and (2) the nature of inhibitory neurotransmission in the IAS. Information produced by these studies will permit an understanding of the pathophysiology that underlies disorders of the LAS, and provide a rationale for development of therapies to treat disorders of the IAS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DEFECATION

NEUROMUSCULAR

CONDITION

THERAPY-DYSSYNERGIC

Principal Investigator & Institution: Rao, Satish S.; Internal Medicine; University of Iowa Iowa City, Ia 52242 Timing: Fiscal Year 2001; Project Start 01-SEP-2000; Project End 30-JUN-2005 Summary: Constipation affects 4 million Americans, predominantly women and the elderly. Its pathophysiology is incompletely understood and its treatment is unsatisfactory. Laxative-dependent, and unable to accomplish natures' call, many resort to desperate treatments. About 50 percent of patients with constipation exhibit uncoordinated or dyssynergic defecation. Uncontrolled studies suggest that biofeedback therapy may improve symptoms in these patients. But, whether the improvement is due to the behavioral intervention or a consequence of excess attention is not known. Biofeedback therapy is labor-intensive, expensive and only available in a few centers. In order to treat the many patients in the community, a home-based, self-training program is essential. Our proposal addresses three objectives; 1) to determine the efficacy of biofeedback therapy by performing a randomized controlled study in patients with dyssynergic defecation. After diagnostic evaluation with colon transit study, anorectal manometry and stool diaries, 90 patients will be randomized to receive standard treatment consisting of diet, habit-training and laxatives or biofeedback therapy consisting of neuromuscular conditioning or sham feedback therapy. Short-term (3 month) and long-term (12 month) assessments of anorectal physiology-defecation index, anal relaxation, fecom expulsion time and colon transit time and symptomatologybowel satisfaction score, straining effort, laxative consumption score and stool form and consistency will be performed. 2) To investigate the efficacy of home-training versus office-based biofeedback therapy and if it is cost-effective, 100 patients will be randomized to receive either home-training using a hand-held portable device and a silicon probe or biofeedback therapy for 3 months. Anorectal physiology and symptoms will be assessed and actuarial costs of each treatment will be compared. 3) For a condition that is entwined with psyche there is no information on quality of life or psychosocial function. We wish to investigate these parameters with validated instruments, SF-36 and SCL-90-R in 90 patients, before and after treatment and compare this with two controlled groups. This may provide impetus for new treatments such as psychotherapy. This first controlled study will determine the efficacy and scientific basis for a safe and alternative therapy for difficult defecation, provide new information that could facilitate home self-training and assess the impact of treatment on anorectal physiology, symptoms, quality of life and psychosocial aspects. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

Studies

•

35

Project Title: NICOTINE & MORPHINE EFFECTS ON DIABETES ONSET & COMPLICATIONS Principal Investigator & Institution: Obih, Patience O.; Xavier University of Louisiana Box 121-C New Orleans, La 70125 Timing: Fiscal Year 2001 Summary: This study is undertaken to investigate the effect of drugs of abuse, morphine and nicotine on diabetes mellitus. Diabetes mellitus is the most common endocrine disease and consumes about 15% of annual health care expenditure in the United States. At the same time 36% of the population smokes cigarette and the opiates also rank high among the commonly abused agents. The long term goal of this study is to examine the hypothesis 1) Acutely or chronically administered nicotine or morphine accelerates the onset of diabetes. 2) Complications of diabetes worsen under the influence of chronically ingested nicotine/morphine. 3) the degenerative processes of diabetes will alter the receptor binding characteristics of morphine and nicotine receptor (ie. opioid receptors, nicotinic receptors and muscarinic receptors). We will examine these hypotheses with the following specific aims in mind: A) To evaluate the effect of morphine and nicotine on the onset of diabetes, rats will be treated with nicotine and morphine acutely or chronically and thereafter challenged with varying doses of streptozotocin (20, 40, 60 mg/kg)) intraperitoneally to induce diabetes. B) To examine the impact of morphine and nicotine on diabetic state, rats will first of all be made diabetic with intraperitonial injection of 60 mg/kg of streptozotocin (STZ). These diabetic rats will then be subjected to chronic administration of nicotine (8 weeks). Some groups of these rats will also be treated with insulin. The control will receive the vehicle. During the eight weeks, parameters to be monitored include: possible occurrence of diarrhea/constipation, body weight, fluid consumption, blood glucose level from an incision on the tail. At the end of the treatment period, animals will be killed by decapitation and parameters such as blood insulin and glucose level, by specific diagnostic kits will be measured, histopathology of the pancreas will also be examined. C) Radio ligand binding studies will be carried out to determine the receptor density of opioid receptors, nicotinic receptors, and muscarinic receptors in the treated and untreated rats. Examining the impact of attention since a significant number of US population and the world population suffer from addiction and may also have diabetes at the same time. The proposed study may increase the understanding of basic mechanisms of drug abuse in diabetes and may provide important practical information for developing new strategies for treatment. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: NOVEL THERAPY AND MEASURE OF OPIOID-INDUCED CONSTIPATION Principal Investigator & Institution: Liu, Maywin; St. Joseph Medical Center (Towson, Md) 7620 York Rd Towson, Md 21204 Timing: Fiscal Year 2001; Project Start 29-SEP-1999; Project End 30-JUN-2002 Summary: Dr. Maywin Liu, Assistant Professor of Anesthesia at the University of Pennsylvania Medical Center, is applying for a Mentored Patient-Oriented Research Career Development Grant. Dr. Liu is committed to an academic career in clinical research, examining the mechanisms and adverse effects of opioids. This proposal will allow Dr. Liu to expand from her previous training in experimental pain research to clinically-based research to become an independent, funded academic investigator. Pain affects up to 80 percent of cancer patients. Many patients can obtain adequate relief with

36

Constipation

the proper use of opioids, however, opioid-related adverse effects often substantially limit pain therapy. Side effects of opioids are difficult to treat as the same receptors responsible for production of analgesia are believed to be responsible for producing the side effects. Constipation is the most common opioid-induced side effect occurring in up to 85 percent of patients. Constipation appears to be chiefly a peripheral effect arising from stimulation of the opioid receptors of the gastrointestinal tract. In our first study, we will evaluate the efficacy of methyl-naltrexone, a peripherally-selective opioid antagonist, for the treatment of opioid-induced constipation in cancer patients. In a double-blind, placebo-controlled, randomized trial, subjects will receive either placebo or active drug for 3 weeks after baseline data is obtained. Efficacy will be assessed using changes in bowel frequency, oral-cecal transit time, and constipation-related symptoms. Constipation has objective, i.e., bowel frequency, and subjective components, e.g., abdominal pain, difficulty passing stool. Although difficult to measure, constipationrelated symptoms are usually the primary concern to patients. Assessing for both bowel frequency and subjective symptoms will result in a more appropriate measurement scale. No scale combining both the clinical signs and subjective symptoms of constipation currently exists. As a result, we have developed the Constipation Measurement Scale (CMS) to assess both the symptoms and clinical signs. In this proposal, we will test the reliability, validity, and responsiveness of the CMS. Using a case-control design, patients who respond "yes" to the question "are you constipated?" and age-matched controls who answer "no" will be asked to complete the CMS daily for one week. Total scores of the CMS and subscores of each part will be correlated to the screening question to assess validity. Comparison of daily response will assess the reliability. Patients who are constipated will be treated with lactulose and asked to continue the daily CMS during this time. Pre- and post-treatment scores will be compared to assess for responsiveness of the scale. These studies will serve as a foundation for future studies examining the role of adverse effects of treatment on pain control. In addition, the mechanisms of opioid adverse effects and analgesia will be further explored with the use of methyl-naltrexone, e.g., contribution of peripheral opioid receptors to analgesia and peripheral vs. central mechanisms of other side effects. The methodologic techniques and research skills developed through formal training and conducting the clinical trials will serve as a foundation for pursuing related research questions as Dr. Liu matures into a fully independent academic clinical investigator. In addition, the study will provide important information about the appropriate treatment of opioid-induced constipation which will have an immediate relevance to the care of the cancer patient. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NURSING MANAGEMENT OF IBS: IMPROVING OUTCOMES Principal Investigator & Institution: Heitkemper, Margaret M.; Professor & Director; Biobehavioral Nursing and Health Systems; University of Washington Seattle, Wa 98195 Timing: Fiscal Year 2003; Project Start 01-AUG-1996; Project End 31-JAN-2007 Summary: (provided by applicant): The proposed application is a competitive supplement to the NINR funded project titled "Nursing Management of IBS: Improving Outcomes". In the United States, it is estimated that 10-20% of the population experience symptoms compatible with a diagnosis of irritable bowel syndrome (IBS). IBS is a functional condition characterized by change in bowel patterns, (e.g., constipation, diarrhea), interfering with functional activities and increasing health care utilization. Current recommended therapies include diet manipulation, self-management, psychotherapy, and motility and pain modulation via pharmacological therapy. The

Studies

37

purpose of the parent project funded in 2002 is 1) to determine whether the CSM intervention is equally effective in men and peri- and postmenopausal women and 2) to determine whether the CSM intervention is as effective when delivered over the telephone as compared to a face-to-face approach. A three-group randomized clinical trial with longitudinal follow-up will be used to test the effectiveness of a face-to-face versus telephone comprehensive self-management (CSM) program relative to a usual care control group. Outcome variables will be measured during the assessment phase (T1) then 6 months (T2) and 12 months (T3) after the randomization phase. The primary aim of this supplement is to compare the distribution of SET polymorphisms across predominate bowel pattern subgroups and gender in people with IBS. We hypothesize that the distribution of SERT polymorphisms (5'-flanking promoter region [5-HTTLPR] and in exon 2 [VNTR]) will differ across predominate bowel pattern subgroups and the distribution of SERT polymorphisms will differ by gender. Exploratory aims of this study include: 1) Evaluate the relationship of SERT polymorphisms to symptom experiences and psychological profile; 2) Test whether the degree of improvement in response to the CSM therapy differs by SERT polymorphism; and 3) Evaluate the relationship of platelet rich plasma 5-HT levels to SERT polymorphisms, predominate bowel pattern. This study will provide information on the potential role of serotonin processing in IBS as well as potential gender and bowel symptom predominance. Such results may ultimately be used to tailor therapies for this common health problem. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: OPIOIDS WITH REDUCED POTENTIAL FOR TOLERANCE Principal Investigator & Institution: Thatcher, Linn N.; Pharmaceutical Sciences; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2002; Project Start 01-JUL-2002 Summary: The treatment for the pain associated with terminal cancer remains poorly treated. Although opioids, such as morphine, can trat the pain, chronic treatment with morphine leads to severe constipation. The goal of this research is to develop novel opioids which will treat severe pain, without leading to constipation. The approach to be used consists of developing opioids with a profile of mu agonism and delta antagonism, a profile shown to reduce the development of tolerance to the antinociceptiv4 effects of mu agonists. Thus the ever increasing dose of opioid will not b required, leading to lower levels of constipation. The current hypotheses is that the aromatic ring of the indolomorphinans and benzylidene-type delta selective opioids leads to a profile of low delta efficience. Thus, if a suitably placed aromatic ring is introduced into the structure of the orvinols (a class of opioids known to bind with high affinity to both mu and delta receptors), a profile of potent mu agonism and delta antagonism will result. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: ORAL R108512 FOR CONSTIPATION IN CHILDREN Principal Investigator & Institution: Winter, Harland S.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2001 Summary: This abstract is not available. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

38

Constipation

•

Project Title: ORPHANIN FQ (OFQ) EFFECTS ON RAT COLONIC MOTILITY Principal Investigator & Institution: Takahashi, Toku; Associate Professor; Surgery; Duke University Durham, Nc 27706 Timing: Fiscal Year 2001; Project Start 01-JUL-1999; Project End 30-JUN-2004 Summary: The endogenous opioid receptor-like 1 (ORL1) ligand, orphanin FQ (OFQ), a heptadecapeptide structurally resembling dynorphin A, has recently been identified in rat brain. However, the physiological role of OFQ in gastrointestinal (GI) tract is unknown. Our preliminary studies have shown that OFQ preferentially stimulates muscular contraction in colon without affecting the motility of upper GI tract in rats. We have demonstrated that OFQ accelerates colonic transit and evokes propulsive colonic movements. In contrast, dynorphin A delays colonic transit and produces nonpropulsive movements. Based on our preliminary studies, we hypothesized that OFQ acts on colonic myenteric plexus and causes contractions by inhibiting an inhibitory ATP neural pathway of the colonic myenteric plexus. Inhibition of this inhibitory neural pathway will result in colonic muscle contraction and accelerates colonic transit. In contrast, Dynorphin A inhibits ACh, SP, NO, VIP and PACAP release and stimulates random non-coordinated muscle contraction resulting in delayed colonic transit. To test this hypothesis, we plan to perform immunohistochemistry to demonstrate that OFQ is present in abundance in the colonic myenteric plexus and demonstrate that OFQ receptors are expressed in the colonic myenteric plexus by in situ hybridization. We will then characterize the neural pathways responsible for the stimulatory action of OFQ on colonic motility and investigate the cellular mechanism mediating the inhibition of an inhibitory pathway by electrophysiological studies. Finally, the inhibitory neurotransmitter inhibited by OFQ will be identified by pharmacological studies as well as immunocytochemistry. In addition, we also plan to compare and contrast the mechanisms of action of OFQ versus dynorphin A on colonic motility. We will demonstrate that OFQ, but not dynorphin A, causes propulsive colonic movements and accelerates colonic transit in vivo. Dynorphin A, but not OFQ, inhibits ACh/SP/NO/VIP/PACAP pathway which mediates the peristaltic reflex. In addition, we will perform combined procedure of in situ hybridization and (immuno)histochemistry to demonstrate that OFQ receptors are present on ATP containing neurons whereas kappa receptors are present on ACh-, SP-, NOS-, VIP-, or PACAP-containing neurons. These studies will shed light on the mechanisms of action of OFQ and dynorphin A on colonic motility. This may have important clinical implications since OFQ or its analogues may be beneficial for the treatment of refractory constipation in humans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

•

Project Title: PILOT--DEVELOPING CLINICAL TRIALS OF NOVEL OPIOID PEPTIDES Principal Investigator & Institution: Carr, Daniel; University of Arizona P O Box 3308 Tucson, Az 857223308 Timing: Fiscal Year 2001 Summary: Rapid, fur-reaching research advances in preclinical opioid chemistry and pharmacology have generated ample, persuasive data that several well-characterized opioid peptide analogs have potential clinical utility. Advantages suggested from preclinical studies of two such compounds, DPDPE and biphalin, compared to opioids is current clinical use include diminished addiction liability, fewer mu-opioid side effects shci as constipation or urinary retention, and therapeutic efficacy in patients

Studies

39

with tolerance to mu-opioid analgestics such as after prior morphine therapy for chronic cancer pain. However, no clinical datanow exist regarding the clinical safety and efficacy of these analgesic peptides, particularly after intrathecal applicaiton although that route is the most appropriate choice for their initial clinical use. Hence, we now request funding for preliminary evaluation of the safety and efficacy of PDDPE and biphalin prior to their initial clinical trials in two clinical pain models, postoperative pain in otherwise healthy patients, and chronic cancer pain in patients with pre-existing intrathecal catheters for morphine delivery. It is our intention, upon successful completion of preclinical toxicologic, kinetic, and distribution studies by our collaborators, to apply for an IND (after a pre-IND meeting at the invitation of the FDA). We shall then seek supplementary funding for Phase 1 and Phase 2 trials in healthy volunteers and patients, respectively. The Phase 2 trials will be prospective, doubleblind, randomized and controlled (controls will receive standard analgesics), conducted in our NIH-funded General Clinical Research Center. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PYRIDOSTIGMINE FOR CONSTIPATION IN PATIENTS W/ AN AUTONOMIC NEUROPATHY Principal Investigator & Institution: Bharucha, Adil E.; Mayo Clinic Rochester 200 1St St Sw Rochester, Mn 55905 Timing: Fiscal Year 2001 Summary: Patients with an autonomic neuropathy frequently have severe constipation unresponsive to our current therapeutic armementarium. We recently demonstrated that i.v. neostigmine increases colonic contractility and transit in healthy volunteers; neostigmine also increased colonic tone and improved symptoms in one patient with autonomic neuropathy and intractable constipation. Pyridostigmine is an acetylcholinesterase inhibitor with higher bioavailability than neostigmine. Hypotheses1) In patients with slow transit constipation due to an autonomic neuropathy resulting from diabetes, pure autonomic failure, an immune-mediated process or multiple system atrophy, the acetylcholinesterase inhibitor pyridostigmine is safe, well tolerated, will improve colonic transit and satisfaction with bowel habits, 2) The effect of intravenous neostigmine on colonic tone during a motility study will predict treatment success with pyridostigmine. Aims - To assess the safety, tolerability, effect on symptoms, colonic transit and satisfaction with bowel movements of pyridostigmine in patients with constipation due to an autonomic neuropathy, and to determine if neostigmine's effects on the colonic pressure-volume relationship during a motility study predict the therapeutic response to pyridostigmine. Methods - Open-label, phase II pilot study of an escalating dose of pyridostigmine (60 mg t.i.d. to 180 mg t.i.d) in 10 patients with an autonomic neuropathy and constipation. A two-week run-in single-blind placebo phase will be followed by a 6-week single-blind treatment phase. Standard clinical assessments and a radionuclide whole-gut transit study will be performed at the beginning and end of the study. The effect of i.v. neostigmine on colonic tone and compliance will be assessed prior to the therapeutic trial. Primary endpoints are the effect of pyridostigmine on colonic transit and patient reported satisfaction with bowel movements during the last 2 weeks of the treatment period. Secondary endpoints are derived from the Rome Criteria for constipation (number of stools/week, stool consistency, frequency of straining and incomplete evacuation) and the proximal colonic emptying rate. A total of 10 patients in this pilot study should provide sufficient information to estimate the response magnitude and variability of the quantitative primary response variable, colonic transit. Significance - A successful therapeutic

40

Constipation

response in >6/10 patients in this pilot study will lead to an placebo-controlled study of pyridostigmine in a similar patient population and perhaps other patient groups with constipation due to an autonomic neuropathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: R108512.03MG/KG SOLUTION IN SUBS WITH FECAL RETENTION Principal Investigator & Institution: Gilger, Mark A.; Associate Professor; Baylor College of Medicine 1 Baylor Plaza Houston, Tx 77030 Timing: Fiscal Year 2001 Summary: Single-dose pharmacokinetic study of 0.03 mg/kg of oral R108512 solution in a minimum of 24 pediatric patients aged >= 4 to