Chronic Abdominal and Visceral PainTheory and Practicee docx

2897_C000a.indd 1 09/26/2006 1:17:36 PM
2897_C000a.indd 2 09/26/2006 1:17:37 PM
edited by
Pankaj Jay Pasricha
University of Texas Medical Branch
Galveston, Texas, U.S.A.
William D. Willis
University of Texas Medical Branch
Galveston, Texas, U.S.A.
G. F. Gebhart
University of Pittsburgh
Pittsburgh, Pennsylvania, U.S.A.
Chronic Abdominal
and Visceral Pain
Theory and Practice
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Preface
If anything ail a man, so that he does not perform his functions, if he have a pain in his bowels even,—for that is
the seat of sympathy,—he forthwith sets about reforming—the world. – Henry David Thoreau (1817–1862)
There is almost no physician who has not encountered the problem of chronic visceral
pain at some point in his or her career. Visceral and abdominal pain is a major clinical problem,
affecting up to 25% of the general U.S. population. It may be part of a well-defined syndrome
such as irritable bowel syndrome or chronic pancreatitis or be the sole or dominant clinical
manifestation as in functional abdominal pain and dyspepsia. Patients with such pain present
to a variety of medical specialists including gastroenterologists, cardiologists (noncardiac
chest pain), gynecologists (pelvic pain syndromes) or urologists (interstitial cystitis etc.),
anesthesiologists. The last two decades have seen impressive progress in the neurobiology of
somatic pain and this is now beginning to be translated into clinical practice with the advent
of several new classes of analgesics, particularly for neuropathic syndromes. By contrast,
despite its prevalence, chronic visceral pain remains poorly understood, leading to significant
difficulty in diagnosis and management. Much of modern medicine has tended to dismiss
chronic visceral pain, in part because changes in function and structure of visceral organs

are more subtle than those seen in somatic structures (a deformed and swollen knee for
instance). Indeed, the term ‘‘functional pain’’ is often used (pejoratively) for these patients,
generally in association with a referral to a clinical psychologist.
The editors of this book feel fortunate and privileged to be able to assemble leading
experts from across the world to write the first definitive and comprehensive work on this sub-
ject and one that is truly ‘‘bench to bedside.’’ Conceptually, this book is divided into four
sections. The first deals with a global overview of visceral pain, its distinctive features and
social impact. The second section, written by many of the authors who have defined the para-
digms in this field, provides a detailed discussion of the neurobiological, immunological,
and psychological basis of visceral pain, as provided by the study of both animal models and
human subjects. The next section deals with the growing array of molecular targets for treat-
ment of visceral pain as well as current conventional and alternative approaches used in the
clinic. The final section consists of a detailed discussion of individual syndromes covering
the gamut of problems encountered by the practicing physician. In most instances, two lead-
ing authorities in the field have provided a state-of-the-art summary of the pathophysiology
and management of these conditions, often bringing unique insight as well as practical tips.
The reader can approach this book in many different ways. For the novice clinician or
researcher, if read as written, it will be an easily understood journey of discovery from basic
anatomic and physiological principles to an understanding of the complex balance of patho-
physiological factors that make up a given clinical syndrome and rational approaches to
treatment of the same. For the expert, individual chapters can be perused with ease for an
in-depth and up-to-date review of the topic. Either way, we are confident that the experience
will be rewarding and stimulating.
It is clear that visceral pain syndromes are complex, possibly more so than their somatic
counterparts. The editors of this book hope that we have been able to put together a compi-
lation of work that will provide the beginning of a rational approach to this symptom and
the recognition of the real suffering it causes.
Pain is real when you get other people to believe in it. If no one believes in it but you, your pain is madness or
hysteria.– Naomi Wolf (b. 1962)
Pankaj Jay Pasricha

William D. Willis
G. F. Gebhart

Contents
Preface iii
Contributors xiii
SECTION I: INTRODUCTION AND OVERVIEW OF VISCERAL AND
ABDOMINAL PAIN
1. Distinctive Clinical and Biological Characteristics of Visceral Pain 1
T. J. Ness
Introduction . . . . 1
Clinical Visceral Pain . . . . 1
Clinical Superficial Pain . . . . 2
Psychophysical Studies of Visceral Sensation . . . . 3
Neuroanatomy of Visceral Pain . . . . 4
Differences in Spinal Pathways . . . . 5
Functional Imaging of Visceral Sensation . . . . 6
Effects of Stress on Visceral Pain . . . . 6
Silent Afferents in the Viscera . . . . 7
Are All Visceral Pains the Same? . . . . 7
References . . . . 8
2.
Epidemiology and Socioeconomic Impact of Visceral and
Abdominal Pain Syndromes 11
Smita L. S. Halder and G. Richard Locke III
Introduction . . . . 11
Abdominal Pain . . . . 11
Specific Visceral and Abdominal Pain Syndromes . . . . 12
Conclusions . . . . 15
References . . . . 15

SECTION II: THE NEUROBIOLOGY AND PSYCHOBIOLOGY
OF CHRONIC VISCERAL PAIN
3. Overview of Pain and Sensitization 17
Michael S. Gold
What is Pain? . . . . 17
Pain Terminology . . . . 18
Summary and Conclusions . . . . 27
References . . . . 27
4.
Neuroanatomy of Visceral Pain: Pathways and Processes 33
Elie D. Al-Chaer and William D. Willis
Peripheral Pathways . . . . 33
Central Pathways . . . . 34
Representation of Visceral Sensation in the Brain . . . . 38
References . . . . 39
5.
The Neurobiology of Visceral Nociceptors 45
Stuart M. Brierley and L. Ashley Blackshaw
Introduction . . . . 45
Irritable Bowel Syndrome . . . . 45
Sensory Innervation of the Gastrointestinal Tract . . . . 46
Conclusions . . . . 60
References . . . . 60
6. Neurochemical and Molecular Basis of Peripheral Sensitization 67
Klaus Bielefeldt
Introduction . . . . 67
Ion Channels as Transducers . . . . 67
Synaptic Transmission . . . . 75
Nerve-Immune Interactions and Peripheral Sensitization . . . . 76
Peripheral Sensitization and Visceral Pain Syndromes . . . . 77

References . . . . 78
7.
Spinal Mechanisms of Visceral Pain and Sensitization 85
Richard J. Traub
Introduction . . . . 85
Visceral Afferent Organization Contributing to
Visceral Pain and Hyperalgesia . . . . 86
Referred Pain and Hyperalgesia: Convergence of the
Somatic and Visceral Body . . . . 88
Measurement of Experimental Visceral Pain and Hyperalgesia . . . . 91
Pharmacology of Spinal Processing of Visceral Pain . . . . 95
Gonadal Hormone Modulation of Visceral Pain . . . . 97
Conclusions and a Hypothesis . . . . 97
References . . . . 98
8.
Animal Models of Visceral Pain 107
David R. Robinson and G. F. Gebhart
Introduction . . . . 107
The Cardiopulmonary System . . . . 109
The Gastrointestinal Tract . . . . 111
The Genitourinary Tract . . . . 116
Closing Notes . . . . 121
References . . . . 121
9.
Measuring Pain and Hyperalgesia in Persistent Pain Conditions with a Special
Emphasis on Irritable Bowel Syndrome 127
Donald D. Price, Michael E. Robinson, and G. Nicholas Verne
Introduction . . . . 127
General Considerations Concerning Pain Measurement . . . . 127
Psychophysical Characterization of Pathophysiological Pain . . . . 128

Testing Visceral and Cutaneous Hyperalgesia in
Irritable Bowel Syndrome Patients . . . . 132
Conclusions and Future Implications . . . . 137
References . . . . 138
10.
Mechanisms of Visceral Sensitization in Humans 141
Abhishek Sharma and Q. Aziz
Background . . . . 141
The Modulation of Pain Perception . . . . 141
Visceral Hypersensitivity . . . . 141
Variability in the Development of Sensitized States . . . . 149
Mechanisms of Visceral Sensitization in Functional Gastrointestinal Disorder . . . . 150
Summary . . . . 154
References . . . . 155
11.
Visceral Pain: Lessons from Functional Brain Imaging 161
Emeran A. Mayer and Bruce Naliboff
Introduction . . . . 161
Review of Published Studies on Brain Responses to
Visceral Stimuli . . . . 161
Conclusions and Future Directions . . . . 171
References . . . . 172
vi Contents
12. The Neural Basis of Referred Visceral Pain 177
Maria Adele Giamberardino and Fernando Cervero
Introduction . . . . 177
Referred Pain Phenomena in the Clinical Context . . . . 177
Referred Pain Phenomena in the Experimental Context . . . . 180
Neurophysiological Basis of Referred Pain . . . . 183
Conclusion . . . . 189

References . . . . 189
13.
From Sensation to Perception: The Gut–Brain Connection 193
Fernando Azpiroz
General Overview . . . . 193
Evaluation of Visceral Sensitivity in Humans . . . . 194
Modulation of Visceral Perception . . . . 197
Dysfunction of the Sensory System: Functional Gut Disorders . . . . 198
References . . . . 201
14.
Stress, Visceral Pain, and the Brain–Gut Connections 205
Yvette Tache
´
and Mulugeta Million
Introduction . . . . 205
Stress-Induced Visceral Hyperalgesia . . . . 205
Stress-Induced Somatic and Visceral Hypoalgesia . . . . 208
CRF/CRF
1
Receptors and the Biochemical Coding of Stress . . . . 209
Brain CRF/CRF
1
-Signaling Pathways in Stress-Related
Visceral Hyperalgesia . . . . 210
Conclusions . . . . 213
References . . . . 213
15.
The Biopsychosocial Continuum in Visceral Pain in Chronic Abdominal and
Visceral Pain: Theory and Practice 221
Douglas A. Drossman

Introduction . . . . 221
The Biopsychosocial Continuum . . . . 222
Pathophysiology . . . . 223
Clinical Presentation Based on Severity of Pain and
Implications for Treatment . . . . 227
Conclusion . . . . 228
References . . . . 229
16.
Chronic Pain and Addiction 231
Howard Heit and Douglas Gourlay
Introduction . . . . 231
Binary Concept of Pain and Addiction . . . . 231
Pain and Opioid Addiction—A Continuum Approach . . . . 232
Basic Science of Addiction . . . . 233
Addiction . . . . 234
Physical Dependence . . . . 234
Tolerance . . . . 234
Basic Concepts in the Use of Opioids . . . . 236
Modified-Release Delivery Systems . . . . 237
Long-acting Drugs . . . . 238
Opioids for Analgesia or Opioid Stabilizing Effect? . . . . 238
Universal Precautions in Pain Medicine . . . . 239
Group I Primary Care Management . . . . 239
Group II Primary Care with Consultative Support . . . . 239
Group III Specialty Referral . . . . 240
Classification of Pain . . . . 240
Specific Pain Condition . . . . 241
Federal Regulations for Prescribing a Scheduled
Controlled Substance . . . . 241
Conclusion . . . . 242

References . . . . 243
Contents
vii
SECTION III: THERAPY FOR VISCERAL PAIN: SCIENTIFIC
BASIS AND PRACTICE ASPECTS
17. Treating Visceral Pain Via Molecular Targets on Afferent Neurons:
Current and Future 245
Peter Holzer
Visceral Pain Therapy: Current and Future . . . . 245
Sensory Neurons and GI Hypersensitivity . . . . 245
Criteria for the Design of Efficacious Sensory Neuron–Targeting Drugs . . . . 246
Three Classes of Sensory Neuron–Targeting Drugs . . . . 247
Sensory Neuron–Specific Receptors and Sensors . . . . 247
Ion Channels Regulating Sensory Nerve Excitability,
Conduction, and Transmission . . . . 253
Receptors Relevant to Afferent Neuron Transmission . . . . 254
Conclusions . . . . 258
References . . . . 259
18.
Management of the Patient with Chronic Abdominal Pain and Clinical Pharmacology of
Nonopioid Drugs 271
Michael Camilleri
Introduction . . . . 271
Establishing a Roadmap . . . . 271
Conclusion . . . . 282
References . . . . 282
19.
Pharmacology and Practice of Opioid Drugs for Visceral Pain 287
Jane C. Ballantyne
Introduction . . . . 287

Pharmacology . . . . 287
Acute Visceral Pain . . . . 291
Long-Term Opioid Treatment and its Liabilities . . . . 291
Psychosomatic Gastrointestinal and Genitourinary Disease . . . . 294
Specific Conditions . . . . 295
Conclusion . . . . 296
References . . . . 297
20.
Clinical Approach to Visceral Cancer Pain 301
Sebastiano Mercadante
Mechanisms . . . . 301
Clinical Implications in Cancer Pain . . . . 301
Treatment . . . . 302
Techniques . . . . 306
Conclusion . . . . 308
References . . . . 308
21.
Neuromodulation Techniques for Visceral Pain from Benign Disorders 311
Charles D. Brooker and Michael J. Cousins
Introduction . . . . 311
Intrathecal Drug Therapy . . . . 312
Electrical Stimulation Techniques . . . . 315
Neurolytic Techniques . . . . 318
References . . . . 319
22.
Psychological Interventions for Patients with Chronic Abdominal and Pelvic Pain 323
Luis F. Buenaver, Robert Edwards, and Jennifer A. Haythornthwaite
Introduction . . . . 323
Biofeedback . . . . 324
Hypnosis . . . . 324

Cognitive Behavior Therapy . . . . 325
Multidisciplinary Treatment . . . . 326
Future Directions . . . . 326
References . . . . 327
viii Contents
23. Complementary and Integrative Medicine Approaches to Visceral Pain 331
Victor S. Sierpina and Indumathi Kuncharapu
Introduction . . . . 331
Case Study . . . . 332
Biological Therapies . . . . 333
Mind–Body Therapies . . . . 335
Manual Therapies . . . . 335
Alternative Systems of Care . . . . 336
Bioenergetic Therapies . . . . 337
Summary . . . . 337
References . . . . 338
SECTION IV: CLINICAL SYNDROMES: PATHOPHYSIOLOGY,
DIAGNOSIS AND MANAGEMENT
24. Irritable Bowel Syndrome and Functional Abdominal Pain Syndromes:
Pathophysiology 341
Andrew W. DuPont and Pankaj Jay Pasricha
Introduction and Nature of the Problem . . . . 341
Is Pain Secondary to Motility Abnormalities in IBS? . . . . 342
Is Pain Secondary to Disturbances in Sensory Processing
(Visceral Hypersensitivity)? . . . . 343
Visceral Hypersensitivity: Central or Peripheral? . . . . 345
Etiopathogenesis of Visceral Hypersensitivity . . . . 350
Conclusions . . . . 353
References . . . . 353
Irritable Bowel Syndrome and Functional Abdominal Pain Syndromes:

Clinical Features and Management 357
Lin Chang and Lucinda Harris
Introduction . . . . 357
Irritable Bowel Syndrome . . . . 358
Functional Abdominal Pain Syndrome . . . . 367
Conclusion . . . . 367
References . . . . 368
25.
Noncardiac Chest Pain: Pathophysiology 373
Premjit S. Chahal and Satish S. C. Rao
Introduction . . . . 373
Conclusion . . . . 378
References . . . . 378
Noncardiac Chest Pain: Clinical Features and Management 381
Ronnie Fass and Ram Dickman
Introduction . . . . 381
History and Clinical Presentation . . . . 381
Epidemiology . . . . 382
Diagnosis . . . . 383
Treatment . . . . 389
Summary . . . . 394
References . . . . 395
26.
Pathophysiology of Functional Dyspepsia 399
Jan Tack
Definitions . . . . 399
Dyspepsia Symptom Pattern . . . . 399
Subgroups of Functional Dyspepsia Patients . . . . 399
Putative Pathophysiological Mechanisms . . . . 400
Pathogenesis of Functional Dyspepsia . . . . 401

References . . . . 402
Dyspepsia: Clinical Features and Management 404
Nimish Vakil
Definitions . . . . 404
Prevalence . . . . 405
Contents
ix
Differential Diagnosis . . . . 405
Clinical Diagnosis . . . . 406
Alarm Features . . . . 406
Management Strategies . . . . 406
References . . . . 411
27.
Pathophysiology and Management of Pain
in Chronic Pancreatitis 415
John H. Winston and Pankaj Jay Pasricha
Background and Nature of The Problem . . . . 415
Pathogenesis of Pain in Chronic Pancreatitis . . . . 415
References . . . . 423
28.
Abdominal Wall Pain 427
David S. Greenbaum
Economic Costs . . . . 427
Prevalence . . . . 428
Nonrecognition of CAWP . . . . 428
Etiologies . . . . 428
Clinical History . . . . 430
Physical Examination . . . . 430
Reliability of Diagnosis . . . . 431
Management . . . . 432

Conclusions . . . . 433
References . . . . 434
29.
Unexplained Visceral Pain in Children: Pathophysiology, Clinical Features,
and Management 437
Robert J. Shulman, Danita Czyzewski, and Margaret Heitkemper
Introduction . . . . 437
RAP - Functional Abdominal Pain and Irritable Bowel Syndrome . . . . 438
Functional Dyspepsia . . . . 447
Summary . . . . 448
References . . . . 448
30.
Functional Biliary Type Pain Syndromes 453
Arnold Wald
Introduction . . . . 453
Definitions . . . . 453
Epidemiology . . . . 453
Gallbladder and Biliary Anatomy and Physiology . . . . 454
Functional (Acalculous) Biliary Type Pain . . . . 454
Postcholecystectomy Functional Biliary Type Pain . . . . 458
Conclusions . . . . 460
References . . . . 460
SECTION V: PELVIC PAIN SYNDROMES
31. Pelvic Pain Syndromes: Pathophysiology 463
Charles H. Hubscher, Harpreet K. Chadha, and Ezidin G. Kaddumi
Introduction . . . . 463
Females . . . . 463
References . . . . 472
32.
Pelvic Pain Syndromes: Clinical Features and Management 479

Jane Moore and Stephen Kennedy
Introduction . . . . 479
Definitions and Epidemiology . . . . 479
Treatment . . . . 486
Vulval Pain . . . . 489
Conclusion . . . . 490
References . . . . 490
x Contents
33. Interstitial Cystitis and Related Painful Bladder Syndromes: Pathophysiology 495
Naoki Yoshimura and Lori A. Birder
Introduction . . . . 495
Disease Process . . . . 495
Conclusion . . . . 512
References . . . . 512
Index . . . . 521
Contents xi

Contributors
Elie D. Al-Chaer Departments of Pediatrics, Neurobiology and Developmental Sciences,
Center for Pain Research, College of Medicine, University of Arkansas for Medical Sciences,
Little Rock, Arkansas, U.S.A.
Q. Aziz Department of Gastrointestinal Science, University of Manchester, Hope Hospital,
Salford, U.K.
Fernando Azpiroz Digestive System Research Unit, University Hospital Vall d’Hebron,
Autonomous University of Barcelona, Barcelona, Spain
Jane C. Ballantyne Department of Anesthesia and Critical Care, Harvard Medical School, and
Division of Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, U.S.A.
Klaus Bielefeldt Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh
Physicians, Pittsburgh, Pennsylvania, U.S.A.
Lori A. Birder Departments of Medicine and Pharmacology, University of Pittsburgh School of

Medicine, Pittsburgh, Pennsylvania, U.S.A.
L. Ashley Blackshaw Department of Gastroenterology, Hepatology and General Medicine,
Nerve-Gut Research Laboratory, Royal Adelaide Hospital, Discipline of Physiology, School of
Molecular and Biomedical Sciences, Department of Medicine, University of Adelaide, Adelaide,
South Australia, Australia
Stuart M. Brierley Department of Gastroenterology, Hepatology and General Medicine, Nerve-Gut
Research Laboratory, Royal Adelaide Hospital, Discipline of Physiology, School of Molecular and
Biomedical Sciences, University of Adelaide, Adelaide, South Australia, Australia
Charles D. Brooker Pain Management Research Institute, Royal North Shore Hospital,
St. Leonard’s, New South Wales, Australia
Luis F. Buenaver Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
School of Medicine, Baltimore, Maryland, U.S.A.
Michael Camilleri Clinical Enteric Neuroscience Translational and Epidemiological Research
(C.E.N.T.E.R.) Program, Mayo Clinic College of Medicine, Rochester, Minnesota, U.S.A.
Fernando Cervero Anesthesia Research Unit (Faculty of Medicine), Faculty of Dentistry and
McGill Center for Pain Research, McGill University, Montreal, Quebec, Canada
Harpreet K. Chadha Department of Anatomical Sciences and Neurobiology, University of
Louisville School of Medicine, Louisville, Kentucky, U.S.A.
Premjit S. Chahal Department of Internal Medicine, University of Iowa Carver College of
Medicine, Iowa City, Iowa, U.S.A.
Lin Chang Center for Neurovisceral Sciences and Women’s Health, Division of Digestive Diseases,
Department of Medicine, David Geffen School of Medicine at UCLA, and VA, Greater Los Angeles
Healthcare System, Los Angeles, California, U.S.A.
Michael J. Cousins Pain Management Research Institute, Royal North Shore Hospital,
St. Leonard’s, New South Wales, Australia
Danita Czyzewski Departments of Psychiatry and Behavioral Sciences and Pediatrics,
Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, U.S.A.
Ram Dickman The Neuro-Enteric Clinical Research Group, Southern Arizona VA Health Care
System, and University of Arizona Health Sciences Center, Tucson, Arizona, U.S.A.
Douglas A. Drossman UNC Center for Functional GI and Psychiatry, Division of

Gastroenterology and Hepatology, University of North Carolina at Chapel Hill,
Chapel Hill, North Carolina, U.S.A.
Andrew W. DuPont Department of Medicine, Division of Gastroenterology and Hepatology,
University of Texas Medical Branch, Galveston, Texas, U.S.A.
Robert Edwards Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
School of Medicine, Baltimore, Maryland, U.S.A.
Ronnie Fass The Neuro-Enteric Clinical Research Group, Section of Gastroenterology, Department
of Medicine, Southern Arizona VA Health Care System, and University of Arizona Health Sciences
Center, Tucson, Arizona, U.S.A.
G. F. Gebhart Center for Pain Research, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A.
Maria Adele Giamberardino Department of Medicine and Science of Aging, ‘‘G. d’Annunzio’’
University of Chieti, Chieti, Italy
Michael S. Gold Department of Biomedical Sciences, Dental School, Program in Neuroscience, and
Department of Anatomy and Neurobiology, Medical School, University of Maryland, Baltimore,
Maryland, U.S.A.
Douglas Gourlay The Wasser Pain Management Center, Mount Sinai Hospital, Toronto,
Ontario, Canada
David S. Greenbaum College of Human Medicine, Michigan State University, Michigan, U.S.A.
Smita L. S. Halder Division of Gastroenterology, Dyspepsia Center, Mayo Clinic College of
Medicine, Rochester, Minnesota, U.S.A.
Lucinda Harris Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale,
Arizona, U.S.A.
Jennifer A. Haythornthwaite Department of Psychiatry and Behavioral Sciences, Johns Hopkins
University School of Medicine, Baltimore, Maryland, U.S.A.
Howard Heit Georgetown University School of Medicine, Washington, D.C., U.S.A.
Margaret Heitkemper Department of Biobehavioral Nursing, University of Washington, Seattle,
Washington, U.S.A.
Peter Holzer Department of Experimental and Clinical Pharmacology, Medical University of Graz,
Graz, Austria
Charles H. Hubscher Department of Anatomical Sciences and Neurobiology, University of

Louisville School of Medicine, Louisville, Kentucky, U.S.A.
Ezidin G. Kaddumi Department of Anatomical Sciences and Neurobiology, University of
Louisville School of Medicine, Louisville, Kentucky, U.S.A.
Stephen Kennedy Nuffield Department of Obstetrics and Gynecology, University of Oxford,
John Radcliffe Hospital, Oxford, U.K.
Indumathi Kuncharapu University of Texas Medical Branch, Galveston, Texas, U.S.A.
G. Richard Locke III Division of Gastroenterology, Dyspepsia Center, Mayo Clinic College of
Medicine, Rochester, Minnesota, U.S.A.
Emeran A. Mayer Center for Neurovisceral Sciences and Women’s Health, David Geffen School of
Medicine at UCLA, Los Angeles, California, U.S.A.
Sebastiano Mercadante Anesthesia and Intensive Care Unit, Pain Relief and Palliative Care Unit,
Law Maddalena Cancer Center, Palermo, Italy
Mulugeta Million CURE/Digestive Diseases Research Center, and Center for Neurovisceral
Sciences and Women’s Health, Division of Digestive Diseases, Department of Medicine,
University of California Los Angeles, and VA Greater Los Angeles Healthcare System,
Los Angeles, California, U.S.A.
xiv
Contributors
Jane Moore Nuffield Department of Obstetrics and Gynecology, University of Oxford,
John Radcliffe Hospital, Oxford, U.K.
Bruce Naliboff VA Greater Los Angeles Healthcare System, Los Angeles, California, U.S.A.
T. J. Ness Department of Anesthesiology, School of Medicine, University of Alabama at
Birmingham, Alabama, U.S.A.
Pankaj Jay Pasricha Department of Internal Medicine, Division of Gastroenterology and
Hepatology, and Enteric Neuromuscular Disorders and Pain Center, University of Texas Medical
Branch, Galveston, Texas, U.S.A.
Donald D. Price Departments of Oral Surgery and Neuroscience, University of Florida Colleges of
Dentistry, Public Health, and Health Professions, and Medicine, and McKnight Brain Institute,
Gainesville, Florida, U.S.A.
Satish S. C. Rao Department of Internal Medicine, University of Iowa Carver College of Medicine,

Iowa City, Iowa, U.S.A.
David R. Robinson Center for Pain Research, University of Pittsburgh, Pittsburgh,
Pennsylvania, U.S.A.
Michael E. Robinson Department of Clinical and Health Psychology, University of Florida
Colleges of Dentistry, Public Health and Health Professions, and Medicine, and McKnight Brain
Institute, Gainesville, Florida, U.S.A.
Abhishek Sharma Department of Gastrointestinal Science, University of Manchester,
Hope Hospital, Salford, U.K.
Robert J. Shulman Department of Pediatrics and Children’s Nutrition Research Center,
Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, U.S.A.
Victor S. Sierpina University of Texas Medical Branch, Galveston, Texas, U.S.A.
Yvette Tache
´
CURE/Digestive Diseases Research Center, and Center for Neurovisceral Sciences
and Women’s Health, Division of Digestive Diseases, Department of Medicine,
University of California Los Angeles, and VA Greater Los Angeles Healthcare System,
Los Angeles, California, U.S.A.
Jan Tack Department of Internal Medicine, Division of Gastroenterology, University Hospital
Gasthuisberg, University of Leuven, Herestraat, Leuven, Belgium
Richard J. Traub Department of Biomedical Sciences and Research Center for Neuroendocrine
Influences on Pain, University of Maryland Dental School, Baltimore, Maryland, U.S.A.
Nimish Vakil University of Wisconsin School of Medicine and Public Health, Madison,
Marquette University College of Health Sciences, Milwaukee, Wisconsin, U.S.A.
G. Nicholas Verne Department of Medicine, University of Florida Colleges of Dentistry, Public
Health and Health Professions, and Medicine, and McKnight Brain Institute, Gainesville,
Florida, U.S.A.
Arnold Wald Department of Medicine, Section of Gastroenterology and Hepatology,
University of Wisconsin School of Medicine and Public Health,
Madison, Wisconsin, U.S.A.
William D. Willis Department of Neuroscience and Cell Biology, University of Texas Medical

Branch, Galveston, Texas, U.S.A.
John H. Winston Department of Internal Medicine, Division of Gastroenterology and Hepatology,
and Enteric Neuromuscular Disorders and Pain Center, University of Texas Medical Branch,
Galveston, Texas, U.S.A.
Naoki Yoshimura Departments of Urology and Pharmacology, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania, U.S.A.
Contributors xv

Section I INTRODUCTION AND OVERVIEW OF VISCERAL AND
ABDOMINAL PAIN
1
Distinctive Clinical and Biological
Characteristics of Visceral Pain
T. J. Ness
Department of Anesthesiology, School of Medicine, University of Alabama at Birmingham,
Alabama, U.S.A.
INTRODUCTION
In the natural sciences, there has long been a continuous conceptual battle between the
‘‘lumpers’’ and the ‘‘splitters’’—those who wish to lump together phenomena with similarities
as variations of an overriding mechanism and those who wish to split observed events into
multiple independent phenomena with their own unique mechanisms. Nowhere is this lum-
per versus splitter dichotomy more apparent than in the field of pain research. Some would
extrapolate all findings related to one type of painful stimulus to all types of painful stimuli
in all sites. Others would claim that there can be no generalization of pathways or function
for any pains arising from different parts of the body. Obviously, there is a middle ground
where general principles may apply to many systems, but there may be mechanisms specific
to individual systems. Such is the case with visceral pain.
Clinically, visceral pain is common. It keeps gastroenterologists, cardiologists, urologists,
gynecologists, general surgeons, and internists of all kinds busy on a daily basis in their
attempt to diagnose and treat its causes. Until recently, our knowledge related to pain arising

from the internal organs of the body was extrapolated from studies related to heating and pok-
ing the surface of the body, but studies in the last two decades gave evidence that this is an
overextrapolation that contains many inaccuracies. There are differences in the clinical experi-
ence of visceral pain when compared with that of cutaneous pain, and these differences have
been confirmed in psychophysical studies comparing the two types of pain. There are also
clear differences in the neurobiology of visceral pain systems when compared with those of
superficial pain systems. This chapter will present an overview of these differences with an
emphasis on human studies, and will defer an in-depth description of basic science studies
to subsequent chapters. This chapter builds on previous reviews of this topic (1–6), and many
primary sources may be found in those other sites. The terms ‘‘superficial’’ and ‘‘cutaneous’’
are used interchangeably, and to avoid ambiguity, the term ‘‘somatic’’ is avoided, since pain
arising in deep, nonvisceral somatic structures such as muscles and joints share many of
the characteristics of pain arising from the internal organs of the body.
CLINICAL VISCERAL PAIN
The viscera, when they are healthy, give rise to minimal conscious sensation. Fullness, gurgles,
and a sensation of gas are the consequences of ingestion or sources of a need for elimination.
In day-to-day activities, these sensations often increase to levels of mild discomfort, but when
viscera become diseased or inflamed, the same stimuli that produce innocuous sensations
can become an overwhelming source of sensations that can stop all activity and can demand
complete attention. Nausea occurs commonly with visceral pains as do other autonomic res-
ponses such as sweating to the point of diaphoresis, piloerection, and dyspnea. It is clinical
lore that visceral pains produce strong emotional responses to the point that they may appear
out of proportion to the perceived intensity of the pain. Strong emotions are not only evoked
by visceral sensations but also serve to evoke further visceral sensations such that a positive
feedback effect is possible with pain producing anxiety, which produces more pain. For this
reason, there is a poor correlation between the amount of definable visceral pathology and
the distress/pain intensity produced by that pathology.
The observation that pathology and symptomatology may not agree is readily apparent
in numerous visceral pain disorders. For example, chronic pancreatitis typically has a defin-
able pathology, but alterations in pain are not consistently correlated with the degree of

changes in radiographic or laboratory findings. Other disorders such as irritable bowel
syndrome, noncardiac chest pain, and postcholecystectomy syndrome appear to have no
histopathological bases and so are termed ‘‘functional.’’ They are often associated with altered
patterns/pressures associated with motility, production of gas, and ingestion of food or
beverage, but measures of ‘‘altered’’ activity are often within physiological limits. Hence the
term ‘‘visceral hypersensitivity’’ was coined to describe discomfort and pain in the absence
of obvious visceral pathology (7).
The clinical feature of visceral pain that is considered its hallmark finding is its poor and
unreliable localization. Researchers and thinkers from Lewis (8) to Procacci et al. (9) to the
present (1–6) have debated concepts of ‘‘true’’ visceral pain versus ‘‘referred’’ visceral pain—
the distinction between them being some element of localization. True visceral pain (or
splanchnic pain) has no structural localization, but referred visceral pain has perceived
localization to nonvisceral sites. Generally stated, visceral pains are deep and diffuse, with
generalized localization to body regions and not to specific organs of origin. Unless experi-
enced on multiple events so that an association is formed between certain sensations and a
particular organ (as in recurrent cardiac angina), often the only organ-related localization that
is possible is when physical examination manipulations serve to directly stimulate the painful
organ or when particular body functions (e.g., urination) lead to the evocation of pain. Visceral
pain originating from a focal pathology can be felt in several different areas at the same time or
can migrate throughout a region even though the site of origin does not appear to change. Sites
of pain sensation, when localized, are typically sensed in deep tissues that receive afferent
inputs at the same spinal segments as visceral afferent entry. Hence, a ‘‘mapping’’ of referred
pain sites can lead to a mapping of visceral afferent pathways. What is called referred pain in
the clinical literature appears to be two separate phenomena: (i) the sensation is transferred to
another site (e.g., angina can be felt in the chest, neck, and arm), and/or (ii) same-segmental
sites become more sensitive to inputs applied directly to those other sites (e.g., flank muscle
becomes sensitive to palpation when passing a kidney stone). The latter phenomenon is also
described as secondary somatic hyperalgesia. Motor responses evoked by visceral stimuli are
also segmental in nature, with a generalized increase in muscle tone to the point of spasm.
Like most other pains, in females, most clinically relevant visceral pains are affected by

the menstrual cycle, with an apparent flare in pain intensity during the perimenstrual period.
This appears to be true for irritable bowel syndrome (10), kidney stones (11), and interstitial
cystitis (12), as well as gynecological pains (13). Arendt-Nielsen et al. (14) examined the effect
of gender and the menstrual cycle on both experimental and visceral pain and found that
normal healthy populations have some gender- or cycle-related effects, but that in subjects
with clinical disease syndromes, these differences and effects are magnified.
CLINICAL SUPERFICIAL PAIN
Superficially applied noxious stimuli appear to produce more consistent responses than
stimuli applied to visceral structures. In contrast to the viscera, the surface of our body con-
tinuously generates conscious sensations, and there is a clear localization of sensations to very
small surface areas. In nonhairy skin areas, adjacent painful stimuli can be discriminated to
within millimeters. Pain can be evoked from any body surface in a reliable fashion, and the
intensity of the evoked stimulus is highly consistent unless actual tissue damage occurs with
secondary inflammation. Likewise, superficial sensations from a specific site are always
reliably localized to the same site and do not ‘‘migrate’’ to other body areas in the absence
of nerve injury. Injury to the surface of our body inspires motion with ‘‘fight or flight’’ beha-
vioral responses, highly localized flexion-withdrawal reflexes, and stimulus-linked alterations
in ongoing activities. Hypersensitivity, when it occurs in superficial structures, is always asso-
ciated with inflammation or nerve injury. All these noted phenomena are different from the
equivalent phenomena evoked by visceral stimuli.
2 Ness
PSYCHOPHYSICAL STUDIES OF VISCERAL SENSATION
To determine whether uncontrolled clinical observations are indeed representative of res-
ponses evoked by visceral pain rather than a nonspecific characterization of chronic pain,
psychophysical studies have been performed using controlled visceral and nonvisceral stimuli
in both healthy subjects and those with clinical diagnoses of painful visceral disorders. Vis-
ceral stimuli have included chemical, electrical, thermal, and mechanical stimuli (15). Most
studies have not attempted to compare responses to visceral stimuli with those evoked by
cutaneous stimuli in a side-by-side comparison. An exception to this is a study by Strigo
et al. (16), which directly compared sensations evoked by balloon distension of the esophagus

with sensations evoked by thermal stimulation of the midchest skin. Using graded intensities
of both distending and thermal stimuli, it was possible to match the intensity of evoked sensa-
tions produced at the two different sites. Consistent with clinical lore, visceral sensations were
poorly localized, and equal intensities of reported sensation produced greater emotional
responses when the visceral stimulus was employed (this will be discussed to a greater extent
below). Normal subjects undergoing urinary bladder distension also report higher unpleasant-
ness ratings than intensity ratings produced by identical levels of visceral stimulation (17). In
the study by Strigo et al. (16), there was a tight temporal link between the thermal cutaneous
stimulus and the evoked sensations. In contrast, there was a poor temporal correlation with
the esophageal stimulus in that a sustained, relatively high intensity of sensation was per-
ceived even after terminating the distending esophageal stimulus. Kwan et al. (18) observed
similar findings related to the temporal correlation between visceral stimuli and sensation
when they examined the sensations evoked by rectal distension in normal subjects. They were
able to simultaneously to measure and control volumes and pressures of distension within a
rectal balloon and had subjects report sensations evoked by this stimulus using a real-time,
computer-driven visual analog scale. In general, visceral sensations outlasted the visceral
stimulus. Further, after five repeated distensions, pain ratings increased markedly as did un-
pleasantness ratings, suggesting a sensitization phenomenon. Other psychophysical studies
have also demonstrated that a sensitization process can occur with sequentially repeated
stimuli. Specifically, repeated distension of the gut may lead to increasing intensities of pain/
discomfort when the same organ is distended (19) and may also sensitize neighboring visceral
structures (20). Hence, in these studies of normal healthy control subjects, a minimally insen-
sate organ became hypersensitive with the presentation of recurrent abnormal afferent input.
Psychophysical studies have demonstrated evidence of hypersensitivity to visceral stim-
uli in virtually all clinically relevant visceral pain disorders. This includes hypersensitivity to
gastric distension in patients with functional dyspepsia (21), intestinal and rectal distension in
patients with irritable bowel syndrome (7,22), biliary and/or pancreatic duct distension
in patients with postcholecystectomy syndrome or chronic pancreatitis (23), and bladder dis-
tension in patients with interstitial cystitis (17). In all cases, pain and/or discomfort were
experienced at intensities of stimulation lower than required to produce the same quality

and intensity of sensation in a healthy population. It is notable that in many cases, the hyper-
sensitivity was limited to the particular organ system being studied. An example of this was
reported by Aspiroz (24), who observed hypersensitivity to gastric distension but normal sen-
sitivity in the duodenum and upon cutaneous testing in subjects with functional dyspepsia.
Others have reported more whole-body effects. For example, Verne et al. (25) reported hyper-
sensitivity to thermal testing in all dermatomes in subjects with irritable bowel syndrome, but
the hypersensitivity was greatest in those dermatomes closest to those corresponding to rectal
‘‘viscerotomes.’’
Evidence of subpopulations within a single clinical diagnosis has also been presented.
Testing of rectal sensitivity in irritable bowel patients using random order, graded distension
found that some subjects test as reliably hypersensitive, with consistent lowering of thresh-
olds independent of the order of stimulus intensity presentation, and others appear to be
hypervigilant, with greater sensitivity associated with progressively increasing intensities of
stimulation (26). A recent study examining the effects of urinary bladder sensations evoked
by distension in subjects with the diagnosis of interstitial cystitis (17) observed possible sub-
populations when thermal thresholds for pain evocation were examined. Both a high–thermal
sensitivity group and a low-normal–thermal sensitivity group were apparent. It is notable
that all psychophysical studies that have measured various psychological factors such as
Distinctive Clinical and Biological Characteristics of Visceral Pain 3
depression, anxiety, and hypervigilance have identified differences between the clinically
diseased populations and their associated healthy controls (17,25). As a consequence,
dissociating potential psychological modifiers of sensory reports from other, more neuro-
physiological pathologies has proved to be a difficult and at sometimes insurmountable
methodological problem.
NEUROANATOMY OF VISCERAL PAIN
Basic science studies have demonstrated that from the level of gross anatomy to the micro-
scopic determination of both peripheral and central afferent terminals, visceral sensory
pathways are diffusely organized and distributed (diagrammatic summary in Fig. 1). Rather
than mimicking the precise organization of cutaneous sensory afferent pathways, which travel
in defined peripheral nerves and extend into a limited number of spinal segmental nerves

organized in a unilateral, somatotopic fashion, visceral sensory afferent nerve fibers originate
from multiple branchings of nerve fascicles organized into weblike plexuses scattered through
the thoracic and abdominal cavities that extend from the prevertebral region to reach the vis-
cera by predominantly perivascular routes. Injection of neuronal tracing agents into focal sites
within viscera may easily result in the labeling of cell bodies in the dorsal root ganglia of 10 or
more spinal levels in a bilaterally distributed fashion (27). The central spinal projections of
visceral afferent neurons have been demonstrated by Sugiura et al. (28) to branch within the
spinal cord and to spread over multiple spinal segments located both rostral and caudal to
the level of entry. In these studies, individual C-fiber cutaneous afferents were demonstrated
to form tight ‘‘baskets’’ of input to the superficial laminae of localized spinal cord segments,
but individual C-fiber visceral afferents were demonstrated to terminate in superficial and
deep laminae bilaterally in more than 10 spinal segments. Visceral afferents have also been
noted to be neurochemically different than cutaneous afferents, with the expression of differ-
ing receptor subtypes for chemical stimuli (29).
Visceral sensory processing is uniquely different from cutaneous sensory processing in
that there are peripheral sites of the visceral neuronal synaptic contact that occurs with the cell
bodies of prevertebral ganglia such as the celiac ganglion, superior mesenteric ganglion, and
Sympathetic
Chain
Prevertebral
Ganglia
Viscera
Dorsal
Root
Ganglia
Spinal
Cord
Medulla
Thalamus
Visceral

Pain
Skin
Spinal
Cord
Thalamus
Superficial
Pain
Dorsal
Root
Ganglia
Plexus
Peripheral
Nerve
VLQ
VLQ
DC
Figure 1 Diagrammatic representation of visceral and superficial pain pathways. Visceral pain pathways are much
more diffuse, with multiple peripheral branchings, pathways through prevertebral ganglia, and the sympathetic chain
to cell bodies residing bilaterally within multiple dorsal root ganglia. Central projections of visceral afferents also
demonstrate significant branching to interact with spinal cord dorsal horn neurons in multiple laminae of multiple
spinal segments. Major projections of these dorsal horn neurons to supraspinal structures then travel via dorsal
column and ventrolateral quadrant pathways. Superficial pain pathways are, in contrast, much more organized, with
distinct peripheral nerves, a limited number of spinal segmental sites of entry, and focal, heavy interaction with a lim-
ited number of dorsal horn neurons. Supraspinal connections of these dorsal horn neurons travel predominantly in the
ventrolateral quadrant.
4 Ness
pelvic ganglion. This synaptic contact can lead to alterations in local visceral function that is
outside of central control. The gut also carries the enteric nervous system as a self-contained
‘‘little brain’’ regulating the complex functions of digestion/absorption.
The location of the dorsal root ganglion neurons innervating the viscera appears to

follow the original location of the structural precursors of the viscera during embryological
development. Thoracic organs arose near somites corresponding to thoracic segments. Most
abdominal organs arose near somites corresponding to mid-to-low thoracic and upper lumbar
spinal segmental structures. Organization appears more complicated in the realm of
urogenital/pelvic structures, where a dual innervation is apparent with afferents from lower
thoracic–upper lumbar segments and from sacral segments. The testes and ovaries both
originate relatively high in the abdomen and so carry with them a thoracic innervation. The
urinary bladder arises from structures that traverse the developing umbilicus and is still con-
nected to it by the residual urachus. It has a similar thoracolumbar innervation, with sensory
inputs extending up to the T10 level. However, like all structures that physically open their
orifices to sacral dermatomes (rectum, genital structures), it also has a dual spinal innervation
that includes local sacral inputs (the pelvic nerve; S2–S4). An apparent ‘‘gap’’ in the inner-
vation of urogenital structures is simply the absence of those nerves associated with the
hindlimb bud (L3–S1). Mixed with spinal innervations are the wandering inputs and outputs
of the vagus nerve and an elaborate local ganglionic circuitry. The result is that pelvic organs
such as the urinary bladder, gynecological structures, and the lower gastrointestinal (GI) tract
have a complex and doubly diffuse neuroanatomy. Taken together, from a macro- to micro-
scopic level, there is an imprecise and diffuse organization of visceral primary inputs that
would be sufficient to explain the imprecise and diffuse localization of visceral events by
the central nervous system. However, upon entering the central nervous system, additional
mechanisms are at work that lead to additional impreciseness. When quantitatively examined,
spinal dorsal horn neurons with visceral inputs have multiple, convergent inputs from other
viscera, from joints, from muscle, and from cutaneous structures. This presents a substrate that
may explain the phenomenon of referred pain as a misinterpretation of spinal dorsal horn
neuronal activity as being due to input from other more commonly activated structures, but
it also means that the convergence of inputs from multiple viscera onto the same spinal neu-
rons further contributes to the impreciseness of the localization of the source of pain, since
activity in these neurons could reflect visceral, myofascial, articular, or cutaneous pathology.
In contrast, neurons with exclusively cutaneous input are commonly identified in the spinal
dorsal horn, in particular from nonhairy skin. As such, there is no ambiguity associated with

the activation of these neurons and a higher order ‘‘interpretation’’ of their activity.
DIFFERENCES IN SPINAL PATHWAYS
Once transmission has occurred at a spinal level, the information must be passed to higher
sites of processing. There is good evidence that visceral pain follows pathways that are differ-
ent from those used for the perception of superficial pain. There now exist at least 10 clinical
reports from six different neurosurgical groups in the United States, Europe, and Asia who
have demonstrated that a midline myelotomy of the spinal cord (ablation of dorsal midline
region) produces analgesia for visceral pain related to pelvic and lower abdominal organs
(30–37) and for upper abdominal organs such as the stomach, pancreas, and hepatobiliary
systems (38,39). Traditionally, it has been taught that the primary pathways for pain-related
information from the dorsal horn of the spinal cord to the brain are via the ventrolateral quad-
rant white matter of the spinal cord. Tracts located within the ventrolateral quadrant include
the classic spinothalamic and spinoreticular tracts as well as the spinomesencephalic and spi-
nohypothalamic tracts. The ventrolateral quadrant of the spinal cord is clearly important for
cutaneous pain sensation because lesions of those areas of white matter lead to pinprick anal-
gesia in contralateral dermatomes below the level of the lesion. It is for this reason that the
observation that surgical lesions of the dorsal midline of the spinal cord produce clinical anal-
gesia was considered so contrary to dogma. Fortunately, there are good basic science data to
support these clinical observations. In primates, dorsal midline lesions reduce the activity of
thalamic neurons evoked by colorectal distension (40). In rats, effects of similar lesions have
been demonstrated to reduce or abolish thalamic neuronal responses and/or behavioral res-
ponses to colorectal distension (30,41), duodenal distension (42), pancreatic stimulation (43),
Distinctive Clinical and Biological Characteristics of Visceral Pain 5
and hypersensitivity following lower extremity osteotomy (44). Whereas dorsal midline lesions
affect visceral inputs to the nucleus gracilis of the medulla (45), these lesions do not affect vis-
ceral inputs to the ventrolateral medulla (41). Hence, it would appear that the dorsal midline
pathway is one of at least two ascending pathways important to the perception of visceral
pain. Spinal neurons with viscerosomatic convergence and axonal extensions into the dorsal
columns have been demonstrated for primates (46) and rats (30).
FUNCTIONAL IMAGING OF VISCERAL SENSATION

Identification of supraspinal central nervous system sites of increased activity during visceral
stimulation has been possible in humans using positron emission tomography and functional
magnetic resonance imaging technologies. Recently reviewed by Derbyshire (47), such studies
have revealed some consistencies, but are most notable for the multitude of sites that demon-
strate increased regional blood flow. Rectal distension and urinary bladder distension both
produce increased blood flow in select areas of the thalamus, hypothalamus, mesencephalon,
pons, and medulla. Cortical sites of processing include the anterior and mid-cingulate cortex,
the frontal and parietal cortices, and in the cerebellum (47,48). The best study of its kind com-
paring visceral pain sensation with cutaneous pain sensation is that of Strigo et al. (49). Similar
to their psychophysical studies described above, these investigators matched the intensity of
pain sensation produced by esophageal distension with that produced by heating of the skin
of the mid-chest region and measured alterations in cerebral blood flow during the differing
types of stimulation. Cutaneous and esophageal pain sensations were associated with a
similar activation of the secondary somatosensory and parietal cortices plus the thalamus,
basal ganglia, and cerebellum. Cutaneous pain evoked a higher activation of the anterior insu-
lar cortex bilaterally than did esophageal pain and also selectively activated the ventrolateral
prefrontal cortex. Esophageal pain led to the activation of the inferior primary somatosensory
cortex bilaterally, the primary motor cortex bilaterally, and a more anterior locus of the anterior
cingulate cortex than cutaneous pain. This all suggests some shared components of sensation
from the same segmental structures, but also a selective activation of some structures by
superficial versus visceral pain.
EFFECTS OF STRESS ON VISCERAL PAIN
When nervous, one feels ‘‘butterflies’’ or ‘‘a pit’’ in the stomach. ‘‘Gut wrenching’’ emotions
can also evoke profound changes in heart rate, breathing, and all other visceral functions.
There is little doubt that the emotional state can alter sensations from and function of the vis-
cera but the reverse situation also appears to be true: visceral pain evokes strong emotions,
stronger than those evoked by equal intensities of superficial pain. This has been demonstrated
in numerous observational studies, but was most definitively demonstrated in the study by
Strigo et al. (16) (discussed above), which compared balloon distension of the esophagus with
thermal stimulation of the mid-chest skin. Matched intensities of both distending and thermal

stimuli were presented and the magnitude of emotional responses was then quantified using
several tools designed to dissect out the affective components of clinical pain. Word selection
from the McGill Pain Questionnaire suggested a stronger affective component to the sensa-
tion evoked by esophageal distension compared with that by the thermal stimulus. Greater
anxiety was evoked by esophageal distension as measured by the Spielberg State-Trait Anxiety
Inventory. Stressful life events have been viewed as classic ‘‘triggers’’ for the evocation of
diffuse abdominal complaints of presumed visceral origin. As a consequence, these findings
suggest that a positive feedback phenomenon can occur where visceral pain produces anxiety,
which increases visceral pain, which in turn increases anxiety, in an unending cycle.
To dissect out purely physiological from psychological mechanisms of pain, we must
sometimes turn to animal models. Unfortunately, there are severe limits to the interpretation
of emotional experiences in animals. As a consequence, there are limited basic scientific data
that can address issues related to the emotional impact of visceral stimuli. It is possible to
demonstrate aversion to a stimulus by demonstrating alterations in behavior performed by
an animal so that it might avoid the experience of such a stimulus but the existent literature
is limited. There is a greater amount of literature related to the easier-to-interpret effects of
6 Ness