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This unique resource focuses on the diagnosis and treatment of painful conditions—both acute and chronic—from a multi-disciplinary perspective. Joined by a team of nearly 200 international contributors representing a wide range of specialties, Dr. Smith presents the best management options within and across specialties. Succinct treatment and therapy guidelines enable you to quickly access clinically useful information, for both inpatient and outpatient pain management.
  • Offers a cross-discipline approach to pain management for a comprehensive view of the best treatment options within and across specialties including internal medicine, gynecology, physical medicine and rehabilitation, orthopedics, and family medicine.
  • Provides succinct treatment and therapy guidelines, enabling you to locate useful information quickly.
  • Organizes guidance on acute and chronic therapies in a templated format, to facilitate consistent, quick-access consultation appropriate for inpatient or outpatient pain management.


Receptor NMDA
Derecho de autor
Herpes zóster
Spinal stenosis
Cardiac dysrhythmia
Knee pain
Sickle-cell disease
Myocardial infarction
Neurogenic claudication
Neck pain
Cognitive therapy
Medical procedure
Olecranon bursitis
Pelvic pain
Failed back syndrome
Optical rotatory dispersion
Pain scale
Aura (symptom)
Shoulder shrug
Family medicine
Trigger point
Referred pain
Postherpetic neuralgia
Tennis elbow
Opioid dependence
Transcutaneous electrical nerve stimulation
Low back pain
Peripheral neuropathy
Abdominal pain
Chest pain
Diabetic neuropathy
Orthopedic surgery
Pain management
N-Methyl-D-aspartic acid
Somatization disorder
Bowel obstruction
Tension headache
Trigeminal neuralgia
Cluster headache
Shoulder problem
Complete blood count
Whiplash (medicine)
Erythrocyte sedimentation rate
Internal medicine
General practitioner
Coronary artery bypass surgery
Local anesthetic
Back pain
Chronic pain
Carpal tunnel syndrome
Complex regional pain syndrome
Multiple sclerosis
Diabetes mellitus
Tricyclic antidepressant
Epileptic seizure
Rheumatoid arthritis
Pelvic inflammatory disease
Positron emission tomography
Non-steroidal anti-inflammatory drug
Magnetic resonance imaging
Interstitial cystitis
Major depressive disorder
Alternative medicine
Hypertension artérielle
Headache (EP)
Phantoms (film)
Delirium tremens
Tool (groupe)
Placebo (homonymie)


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First Edition
Associate Professor of Anesthesiology, Internal Medicine,
Physical Medicine and Rehabilitation, Albany Medical College
Academic Director of Pain Management, Department of
Anesthesiology, Albany Medical Center
Assistant Director of Clinical Research at, The Pharmaceutical
Research Institute, Albany College of Pharmacy, Albany, New
Saunders ElsevierCopyright
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Copyright © 2009 by Saunders, an imprint of Elsevier Inc.
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Knowledge and best practice in this Aeld are constantly changing. As new
research and experience broaden our knowledge, changes in practice, treatment,
and drug therapy may become necessary or appropriate. Readers are advised to
check the most current information provided (i) on procedures featured or (ii) by
the manufacturer of each product to be administered to verify the recommended
dose or formula, the method and duration of administration, and
contraindications. It is the responsibility of the practitioner, relying on his or her
own experience and knowledge of the patient, to make diagnoses, to determine
dosages and the best treatment for each individual patient, and to take all
appropriate safety precautions. To the fullest extent of the law, neither the
Publisher nor the Authors assumes any liability for any injury and/or damage to
persons or property arising out of or related to any use of the material contained
in this book.
The Publisher
Library of Congress Cataloging-in-Publication Data
Current therapy in pain / [edited by] Howard S. Smith. – 1st ed.
p. ; cm.Includes bibliographical references and index.
ISBN 978-1-4160-4836-7
1. Pain–Treatment. I. Smith, Howard S.,
1956[DNLM: 1. Pain–therapy. WL 704 C9758 2009]
RB127.C92 2009
616’.0472–dc22 2008008166
Executive Publisher: Natasha Andjelkovic
Editorial Assistant: Isabel Trudeau
Design Direction: Steven Stave
Printed in United States of America
Last digit is the print number: 9 8 7 6 5 4 3 2 1D e d i c a t i o n
I would like to dedicate this book to the memory of my mother, Arlene; to my
wife Joan, and our children, Alyssa, Joshua, Benjamin, and Eric; and to my father
Nathan, and stepmother Priscilla.Contributors
Salahadin Abdi, MD, PhD, Professor and Chief,
University of Miami Pain Center, Department of
Anesthesiology, Perioperative Medicine and Pain
Management, University of Miami Miller School of
Medicine, Miami, Florida, PAINFUL DIABETIC
Janet Abrahm, MD, Associate Professor of Medicine,
Harvard Medical School; Director, Pain and Palliative
Care Program, Dana-Farber Cancer Institute and
Brigham and Women’s Hospital, and Division Chief,
Palliative Care, Dana-Farber Cancer Institute, Boston,
Sanjeev Agarwal, MD, Assistant Professor, and Director,
Interventional Physiatry, SUNY Downstate Medical
Center, Brooklyn, New York, STEROIDS; SYMPATHETIC
Phillip J. Albrecht, PhD, Assistant Professor, Center for
Neuropharmacology and Neuroscience, Albany Medical
College; Integrated Tissue Dynamics, LLC, Albany New
Catalina Apostol, MD, Resident in Pain/Anesthesiology,
Department of Anesthesiology, University of Miami,
Charles E. Argoff, MD, Professor of Neurology, AlbanyMedical College; Director, Comprehensive Pain
Program, Albany Medical Center, Albany, New York,
Joseph F. Audette, MA, MD, Assistant Professor,
Department of Physical Medicine and Rehabilitation,
Harvard Medical School, Boston, Massachusetts,
Mark L. Baccei, PhD, Research Assistant Professor,
Department of Anesthesiology, University of Cincinnati
College of Medicine, Cincinnati, Ohio,
Misha-Miroslav Backonja, MD, Professor, Department of
Neurology, Anesthesiology and Rehabilitation
Medicine, University of Wisconsin School of Medicine
and Public Health; Professor, University of Wisconsin
Hospital and Clinics, Madison, Wisconsin,
Zahid H. Bajwa, MD, Assistant Professor of Anesthesia
and Neurology, Harvard Medical School; Director,
Education and Clinical Pain Research, Beth Israel
Deaconess Medical Center, Boston, Massachusetts,
Jeffrey R. Basford, MD, PhD, Professor of Physical
Medicine and Rehabilitation, Department of Physical
Medicine and Rehabilitation, Mayo Clinic, Rochester,
Allison Baum, DPT, Spinal Cord Injury Peer Mentor
Coordinator, St. Charles Hospital and RehabilitationCenter, Port Jefferson, New York, PHYSICAL MEDICINE
Joseph M. Bellapianta, MD, MS, Department of
Orthopaedic Surgery, Albany Medical Center, Albany,
Rafael Benoliel, BDS, LDS, RCS (Eng), Professor and
Chairman, Department of Oral Medicine, Faculty of
Dental Medicine, Hadassah Hebrew University,
Jerusalem, Israel, OROFACIAL PAIN
Karen Bjoro, PhD(c), RN, Doctoral Student, The
University of Iowa, Iowa City, Iowa; Nurse Researcher,
Department of Orthopedics, Neurology and
Neurosurgery, Ulleval University Hospital, Oslo,
Didier Bouhassira, MD, Université de Versailles Saint
Quentin, Versailles; Research Director, INSERM (U 792),
Centre d’Evaluation et de Traitement de la Douleur,
Hôpital Ambroise Paré, Boulogne, France, BRAIN
Daniel Brookoff, MD, PhD, Director, Center for Medical
Pain Management, Presbyterian/St. Luke’s Medical
Center, Denver, Colorado, GENITOURINARY PAIN
Patricia Bruckenthal, PhD, RN, ANP-C, Clinical
Associate Professor, Stony Brook University School of
Nursing; Nurse Practitioner, Pain and Headache
Treatment Center, Department of Neurology, North
Shore/Long Island Jewish Health System, Manhasset,
Sean Burgest, MD, Medical Director, The Burgest Clinic,Austin, Texas, FAILED BACK SURGERY SYNDROME
Allen L. Carl, MD, Professor of Orthopaedic Surgery and
Pediatrics, Albany Medical College, Albany, New York,
Juan Cata, MD, Resident, Institute of Anesthesiology,
Critical Care, and Comprehensive Pain Management,
Cleveland Clinic, Cleveland, Ohio, INTERPLEURAL
Brian D. Cauley, MD, MPH, Resident, Department of
Anesthesiology and Critical Care, Massachusetts
General Hospital, Harvard Medical School, Boston,
Lucy Chen, MD, Instructor, Harvard Medical School;
Attending Physician, Massachusetts General Hospital,
Boston, Massachusetts, OPIOID TOLERANCE,
Jianguo Cheng, MD, PhD, Staff, Department of Pain
Management, Institute of Anesthesiology, Critical Care,
and Comprehensive Pain Management, Cleveland
Pradeep Chopra, MD, MHCM, Assistant Professor
(Clinical), Brown Medical School, Providence, Rhode
Island; Assistant Professor (Adjunct), Boston University
Medical Center, Boston, Massachusetts, THORACIC PAIN
Paul J. Christo, MD, MBA, Assistant Professor, Johns
Hopkins University School of Medicine; Director,
Multidisciplinary Pain Fellowship, and Director, Pain
Treatment Center, The Johns Hopkins Hospital,
Daniel Ciampi de Andrade, MD, Université de Versailles
Saint Quentin, Versailles; Clinical Fellow, INSERM (U792), Centre d’Evaluation et de Traitement de la
Douleur, Hôpital Ambroise Paré, Boulogne, France,
Eli Cianciolo, MD, Clinical Instructor and Pain Medicine
Fellow, Harvard Medical School, and Massachusetts
General Hospital, Boston, Massachusetts,
Daniel Clayton, MD, PhD, Resident, Division of
Neurosurgery, Duke University Medical Center, Durham,
Steven P. Cohen, MD, Associate Professor, Department
of Anesthesiology, and Director of Medical Education,
Johns Hopkins University School of Medicine,
Baltimore, Maryland; Director of Pain Research and
Colonel, United States Army, Walter Reed Army Medical
Center, Washington, DC, SPINAL ANALGESIA
Alane B. Costanzo, MD, Anesthesiology Resident,
University of Miami Miller School of Medicine, Jackson
Memorial Hospital, Miami, Florida, EPIDURAL STEROID
Sukdeb Datta, MD, DABIPP, FIPP, Associate Professor,
and Program Director, Vanderbilt University Pain
Medicine Fellowship, Vanderbilt University Medical
Center; Director, Vanderbilt University Interventional
Pain Center, Nashville, Tennessee, EPIDURAL
Emily A. Davis, MSN, ACNP, Division of Neurosurgery,
Duke University Medical Center, Durham, North
Timothy R. Deer, MD, President and Chief ExecutiveOfficer, The Center for Pain Relief; Clinical Professor,
West Virginia University, Charleston, West Virginia,
Martin L. DeRuyter, MD, Associate Professor of
Anesthesiology and Staff Anesthesiologist, University of
Kansas Medical Center, University of Kansas School of
Medicine, Kansas City, Kansas, PERIOPERATIVE
Anthony Dragovich, MD, Director, Pain Management
Center, Womack Army Medical Center, Fort Bragg,
North Carolina; Assistant Professor, Department of
Anesthesiology, Uniformed Services University of the
Health Sciences, Bethesda, Maryland, SPINAL
Andrew Dubin, MD, MS, Associate Professor of Physical
Medicine and Rehabilitation, Albany Medical College;
Attending Physician, Albany Medical Center Hospital;
Medical Director, Capital Region Spine, Albany, New
Demetri Economedes, DO, Department of Orthopaedic
Surgery, Albany Medical Center, Albany, New York,
Eli Eliav, DMD, PhD, Professor and Director, Division of
Orofacial Pain, and Susan and Robert Carmel Endowed
Chair in Algesiology, University of Medicine and
Dentistry of New Jersey-New Jersey Dental School,
Newark, New Jersey, OROFACIAL PAIN
Jennifer A. Elliott, MD, Assistant Professor, Department
of Anesthesiology, University of Missouri-Kansas City
School of Medicine; Staff Pain Physician, Saint Luke’s
Hospital, Kansas City, Missouri, PATIENT-CONTROLLED
ANALGESIA; α2-AGONISTSNasr Enany, MD, Assistant Professor and Attending
Anesthesiologist, University of Cincinnati, Cincinnati,
Jonathan Epstein, MD, MA, Fellow, Obstetric
Anesthesia, Mount Sinai Medical Center, New York,
Ike Eriator, MD, MPH, Associate Professor, University of
Mississippi School of Medicine; Chief, Pain Management
Services, University of Mississippi Medical Center,
Jackson, Mississippi, CANCER PAIN MANAGEMENT
David Euler, LicAc, Co-Director, Continuing Medical
Education Course, Harvard Medical School, Boston,
Vania E. Fernandez, MD, Assistant Professor of
Anesthesiology, University of Miami School of Medicine;
Pain Management Fellow, Department of
Anesthesiology, Perioperative Medicine and Pain
Management, Jackson Memorial Hospital, Miami,
Richard Field, MD, Pain Fellow, Massachusetts General
Hospital, and Harvard Medical School, Boston,
Nanna Brix Finnerup, MD, Associate Research Professor,
Aarhus University, Aarhus, Denmark, SPINAL CORD
Colleen M. Fitzgerald, MD, Assistant Professor, Feinberg
School of Medicine, Northwestern University; Medical
Director, Women’s Health Rehabilitation,
Rehabilitation Institute of Chicago, Chicago, Illinois,
Marc D. Fuchs, MD, Associative Clinical Professor,Department of Orthopaedic Surgery, Albany Medical
College, Albany, New York, HIP PAIN
Aimee Furdyna, BS, Department of Orthopaedic Surgery,
Albany Medical Center, Albany, New York, BACK PAIN
Christine Gallati, BS, Research Assistant,
Pharmaceutical Research Institute at Albany College of
Pharamacy, Albany, New York, PAIN AND SLEEP
Padma Gulur, MD, Pain Specialist, Center for Pain
Medicine, Massachusetts General Hospital; Instructor in
Anesthesia, Harvard Medical School, Boston,
Massachusetts, PAIN IN CHILDREN
Payam Hadian, BA, College of Arts and Sciences,
University of Rochester, Rochester, New York,
R. Norman Harden, MD, Director, Center for Pain
Studies, and Addison Chair, Rehabilitation Institute of
Chicago; Associate Professor, Feinberg School of
Medicine, Northwestern University, Chicago, Illinois,
Keela Herr, PhD, RN, FAAN, AGSF, Professor and Chair,
Adult and Gerontology, The University of Iowa College
of Nursing, Iowa City, Iowa, Assessment of Pain in the
Nonverbal and/or Cognitively Impaired Older Adult
Greg Hobelmann, MD, Postdoctoral Fellow, Division of
Pain Medicine, Department of Anesthesiology and
Critical Care Medicine, Johns Hopkins University School
of Medicine, Baltimore; Pain Medicine Specialists, P.A.,
Towson, Maryland, PELVIC PAIN
Steven H. Horowitz, MD, Clinical Professor of
Neurology, University of Vermont College of Medicine,
Burlington, Vermont; Assistant in Neurology,Massachusetts General Hospital, Boston, Massachusetts,
Christina K. Hynes, MD, Clinical Instructor, Feinberg
School of Medicine, Northwestern University; Attending
Physician, Rehabilitation Institute of Chicago, Chicago,
Kenneth C. Jackson, II, PharmD, Associate Professor,
Pacific University School of Pharmacy; Associate Editor,
Journal of Pain and Palliative Care Pharmacotherapy,
Chauncey T. Jones, MD, Resident, Department of
Anesthesiology and Critical Care Medicine, Johns
Hopkins University School of Medicine, Baltimore,
Douglas Keene, MD, Director of Pain Management,
Department of Anesthesia, Milton Hospital, Milton,
Massachusetts; Co-founder, Boston PainCare, Waltham,
Kenneth L. Kirsh, PhD, Assistant Professor, Pharmacy
Practice and Science, University of Kentucky; Attending
Clinical Psychologist, The Pain Treatment Center of the
Bluegrass, Lexington, Kentucky, POTENTIAL
Jan Kraemer, MD, Clinical Fellow, Harvard Medical
School, Boston, Massachusetts, HEADACHES OTHER
Michael A. Krieves, BS, Department of Orthopaedic
Surgery, Albany Medical Center, Albany, New York, HIP
PAIN; KNEE PAINClete A. Kushida, MD, PhD, RPSGT, Director, Stanford
University Center for Human Sleep Research; Associate
Professor, Stanford University Medical Center, Stanford
University Center of Excellence for Sleep Disorders,
Stanford, California, PAIN AND SLEEP
Elizabeth Demers Lavelle, MD, Assistant Professor, SUNY
Upstate Medical University, Syracuse, New York, HAND
Lori A. Lavelle, DO, Staff Physician, Altoona Arthritis
and Osteoporosis Center, Duncansville, Pennsylvania,
William F. Lavelle, MD, Assistant Professor, Department
of Orthopaedic Surgery, SUNY Upstate Medical
University, Syracuse, New York, HAND PAIN; BACK
Andrew Linn, MD, Clinical Fellow in Anesthesia,
Harvard Medical School, and Beth Israel Deaconess
Medical Center, Boston, Massachusetts, TRIGEMINAL
Dave Loomba, MD, Assistant Professor, University of
California, Davis, Sacramento; Anesthesiologist, Enloe
Medical Center, Chico, California, SACROILIAC JOINT
Karan Madan, MBBS, MPH, Instructor in Anaesthesia,
Harvard Medical School; Staff, Pain Management
Center, Department of Anesthesia, Perioperative and
Pain Medicine, Brigham and Women’s Hospital, Boston,
TO HIV INFECTIONGagan Mahajan, MD, Associate Professor, and Director,
Fellowship in Pain Medicine, University of California,
Davis, Sacramento, California, SACROILIAC JOINT PAIN
Jianren Mao, MD, PhD, Associate Professor, Harvard
Medical School; Attending Physician, Massachusetts
General Hospital, Boston, Massachusetts, OPIOID
John D. Markman, MD, Director, Neuromedicine Pain
Management Center and Translational Pain Research,
Department of Neurosurgery, University of Rochester
School of Medicine and Dentistry, Rochester, New York,
Eric M. May, MD, Assistant Professor of Anesthesiology,
University of Missouri-Kansas City; Staff
Anesthesiologist, Saint Luke’s Hospital, Kansas City,
Gary McCleane, MD, FFARCSI, Consultant in Pain
Management, Rampark Pain Centre, Lurgan, Northern
Ireland, United Kingdom, PAIN IN THE ELDERLY;
†James McLean, MD , Pain Fellow, Rehabilitation
Institute of Chicago; Department of Physical Medicine
and Rehabilitation, Feinberg School of Medicine,
Northwestern University, Chicago, Illinois, PHYSICAL
Sangeeta R. Mehendale, MD, PhD, Research Associate,
Department of Anesthesia and Critical Care, Pritzker
School of Medicine, University of Chicago, Chicago,
OPIOID USEHarold Merskey, DM, FRCPC, FRCPsych, Professor
Emeritus of Psychiatry, University of Western Ontario,
London, Ontario, Canada, THE TAXONOMY OF PAIN
Tobias Moeller-Bertram, MD, Assistant Clinical
Professor, Department of Anesthesiology, University of
California, San Diego, La Jolla, California, BOTULINUM
Mila Mogilevsky, DO, PT, Resident Physician,
Rehabilitation Institute of Chicago, Department of
Physical Medicine and Rehabilitation, Northwestern
University, Chicago, Illinois, PHYSICAL MEDICINE
Xavier Moisset, MD, Université de Versailles Saint
Quentin, Versailles; Clinical Fellow, INSERM (U 792),
Centre d’Evaluation et de Traitement de la Douleur,
Hôpital Ambroise Paré, Boulogne, France, BRAIN
Muhammad A. Munir, MD, Chairman, Southwest Ohio
Pain Institute, West Chester, Ohio, STEROIDS;
Beth B. Murinson, MS, MD, PhD, Assistant Professor of
Neurology, Johns Hopkins University School of
Medicine; Active Staff, Johns Hopkins Medical
Institutions, The Johns Hopkins Hospital, Baltimore,
Lida Nabati, MD, Instructor of Medicine, Harvard
Medical School; Attending Physician, Division of
Palliative Care, Dana-Farber Cancer Institute, Boston,
POPULATIONSrdjan S. Nedeljković, MD, Fellowship Director, Pain
Medicine Program, and Staff, Pain Management Center,
Department of Anesthesia, Perioperative and Pain
Medicine, Brigham and Women’s Hospital; Assistant
Professor of Anaesthesia, Harvard Medical School,
Boston, Massachusetts, PAIN AND PAIN MANAGEMENT
Lisa J. Norelli, MD, MPH, MRCPsych, Assistant Professor
of Psychiatry, Albany Medical College; Director of
Psychiatry, Capital District Psychiatric Center, Albany,
Akiko Okifuji, PhD, Professor of Anesthesiology, and
Attending Psychologist, Pain Management Center,
University of Utah, Salt Lake City, Utah,
Ike Onyedika, BS, Department of Orthopaedic Surgery,
Albany Medical Center, Albany, New York, HAND PAIN
Susan Elizabeth Opper, MD, Assistant Professor of
Medicine, University of Missouri-Kansas City School of
Medicine; Director, Pain Management Services, Saint
Luke’s Hospital, Kansas City, Missouri, NECK PAIN
Richard K. Osenbach, MD, Director, Neurosurgical
Services, Cape Fear Valley Medical Center, Fayetteville,
Joshua Pal, MD, Clinical Fellow, Harvard Medical
School, Boston, Massachusetts, HEADACHES OTHER
Marco Pappagallo, MD, Professor, Department of
Anesthesiology, Mount Sinai School of Medicine;
Director, Pain Medicine Research and Development,
Mount Sinai Medical Center, New York, New York,
Amar Parikh, Research Assistant, Albany Medical
College, Albany, New York, POST AMPUTATION PAIN
Winston C.V. Parris, MD, FACPM, Professor of
Anesthesiology, and Director, Pain Programs, Duke
University Medical Center; Division Chief, Duke Pain
and Palliative Care Center, Duke University Hospital,
Durham, North Carolina, CANCER PAIN MANAGEMENT
Steven D. Passik, PhD, Associate Professor of Psychiatry,
Weill College of Medicine, Cornell University Medical
Center; Associate Attending Psychologist, Memorial
Sloan Kettering Cancer Center, New York, New York,
Gira Patel, LicAc, Clinical Associate, Osher Integrative
Care Center, Harvard Medical School Osher Institute;
Division for Research and Education in Complementary
and Integrative Medical Therapies, Arnold Pain Clinic,
Beth Israel Deaconess Hospital, Boston, Massachusetts,
Eric M. Pearlman, MD, PhD, Director, Pediatric
Education, and Assistant Professor of Pediatrics, Mercer
University School of Medicine; Savannah Neurology,
P.C., Savannah, Georgia, MIGRAINE HEADACHES
Richard A. Pertes, DDS, Clinical Professor, Division of
Orofacial Pain, University of Medicine and Dentistry of
New Jersey-New Jersey Dental School, Newark, New
Annie Philip, MD, Assistant Professor, Department of
Anesthesiology, University of Rochester School of
Medicine and Dentistry, Rochester, New York,
Mark Anthony Quintero, MD, Pain Management Fellow,
Department of Anesthesiology, Perioperative Medicine
and Pain Management, University of Miami Miller
School of Medicine, Jackson Memorial Hospital, Miami,
Lynn Rader, MD, Clinical Instructor, Feinberg School of
Medicine, Northwestern University; Attending
Physician, Rehabilitation Institute of Chicago, Chicago,
Lakshmi Raghavan, PhD, Associate Director, Research
and Development, Vyteris Corporation, Inc. Fair Lawn,
Rakesh Ramakrishnan, BS, Department of Orthopaedic
Surgery, Albany Medical Center, Albany, New York, HIP
Alan M. Rapoport, MD, Clinical Professor of Neurology,
David Geffen School of Medicine at UCLA, Los Angeles,
California; Founder and Director Emeritus, The New
England Center for Headache, P.C., Stamford,
Rahul Rastogi, MD, Assistant Professor, Washington
University in St. Louis; Assistant Professor and
Attending Anesthesiologist, Barnes-Jewish Hospital, St.
Scott S. Reuben, MD, Professor of Anesthesiology and
Pain Medicine, Tufts University School of Medicine,
Boston; Director, Acute Pain Service, Baystate Medical
Center, Springfield, Massachusetts, PERIOPERATIVE USE
Frank L. Rice, PhD, Professor, Center for
Neuropharmacology and Neuroscience, Albany MedicalCollege; Integrated Tissue Dynamics, LLC, Albany, New
Melissa A. Rockford, MD, Assistant Professor of
Anesthesiology, University of Kansas Medical Center,
University of Kansas School of Medicine, Kansas City,
Carl Rosati, MD, Associate Professor of Surgery, Albany
Medical College; Trauma Director, Albany Medical
Center, Albany, New York, ABDOMINAL PAIN
Mike A. Royal, MD, JD, MBA, Vice President, Clinical
Development - Analgesics, Cadence Pharmaceuticals,
Inc., San Diego, California, ACETAMINOPHEN
Christine N. Sang, MD, MPH, Director, Translational
Pain Research, Brigham and Women’s Hospital, Harvard
Medical School, Boston, Massachusetts, GLUTAMATE
Nalini Sehgal, MD, FABPMR, Associate Professor,
Department of Orthopedics and Rehabilitation,
University of Wisconsin School of Medicine and Public
Health; Medical Director, Interventional Pain Program,
and Pain Fellowship Program Director, University of
Wisconsin Hospital and Clinics, Madison, Wisconsin,
Ashutosh Sharma, PhD, Chief Strategic Officer, Vyteris,
Inc., Fair Lawn, New Jersey, PAIN IN CHILDREN
Lee S. Simon, MD, Associate Clinical Professor of
Medicine, Harvard Medical School, Beth Israel
Deaconess Medical Center, Boston, Massachusetts,
Thomas T. Simopoulos, MD, Instructor in Anaesthesia,
Harvard Medical School; Director of Interventional PainManagement, Beth Israel Deaconess Medical Center,
Boston, Massachusetts, FAILED BACK SURGERY
Jeremy C. Sinkin, BA, Department of Neurosurgery,
University of Rochester School of Medicine and
Dentistry, Rochester, New York, LUMBAR SPINAL
David J. Skinner, MD, Assistant Professor, Departments
of Anesthesiology and Pain Management, Mount Sinai
School of Medicine; Assistant Professor, Mount Sinai
Medical Center, New York, New York, TRAMADOL
Michelle Skinner, MS, Graduate Student, Department of
Psychology, University of Utah, Salt Lake City, Utah,
Howard S. Smith, MD, FACP, FACNP, Associate Professor
of Anesthesiology, Internal Medicine, Physical Medicine
and Rehabilitation, Albany Medical College, Academic
Director of Pain Management, Department of
Anesthesiology, Albany Medical Center, Assistant
Director of Clinical Research at The Pharmaceutical
Research Institute, Albany College of Pharmacy, Albany,
Paul E. Spurgas, MD, Associate Professor of
Neurosurgery, Division of Neurosurgery, Albany Medical
Center, Albany, New York; Temple University,
Steven C. Stain, MD, Neil Lempert Professor, and Chair,
Department of Surgery, Albany Medical College; Chief
of Surgery, Albany Medical Center Hospital, Albany,
Steven Stanos, DO, Assistant Professor, Feinberg School
of Medicine, Northwestern University; Medical Director,
Rehabilitation Institute of Chicago, Chicago, Illinois,
Roland Staud, MD, Professor of Medicine, University of
Florida, Gainesville, Florida, FIBROMYALGIA
Richard L. Uhl, MD, Professor of Surgery, Albany
Medical College, Albany; Adjunct Professor of
Biomedical Engineering, Rensselaer Polytechnic
Institute, Troy; Chief, Orthopaedic Surgery, Albany
Medical Center Hospital, Albany, New York, SHOULDER
Mark Wallace, MD, Professor of Clinical Anesthesiology,
and Program Director, Center for Pain Medicine,
Department of Anesthesiology, University of California,
San Diego, La Jolla, California, BOTULINUM TOXINS
Deirdre M. Walsh, DPhil, BPhysio, Professor of
Rehabilitation Research, Health and Rehabilitation
Sciences Research Institute, University of Ulster,
Newtownabbey, County Antrim, Northern Ireland,
Chris Warfield, BA, Research Assistant, Arnold Pain
Management Center, Beth Israel Deaconess Medical
Center, Boston, Massachusetts, COGNITIVE THERAPY
FOR CHRONIC PAINAjay D. Wasan, MD, MSc, Assistant Professor, Harvard
Medical School; Departments of Anesthesiology and
Psychiatry, Brigham and Women’s Hospital, Boston,
Lynn R. Webster, MD, FACPM, FASAM, Medical Director,
Lifetree Clinical Research and Pain Clinic, Salt Lake
Richard Whipple, MD, Assistant Clinical Professor,
Department of Orthopaedic Surgery, Albany Medical
College, Albany, New York, HAND PAIN
Joshua Wootton, MDiv, PhD, Assistant Professor,
Department of Anaesthesia, Harvard Medical School;
Director of Pain Psychology, Arnold Pain Management
Center, Beth Israel Deaconess Medical Center, Boston,
James P. Wymer, MD, PhD, Assistant Professor of
Neurology, Albany Medical College; Upstate Clinical
Research, Albany, New York, GLUTAMATE RECEPTOR
Chun-Su Yuan, MD, PhD, Cyrus Tang Professor,
Department of Anesthesia and Critical Care, Pritzker
School of Medicine, University of Chicago, Chicago,
Jun-Ming Zhang, MD, MSc, Associate Professor and
Director of Research, Department of Anesthesiology,
University of Cincinnati College of Medicine,
YiLi Zhou, MD, PhD, Courtesy Clinical Assistant
Professor, University of Florida; Medical Director,
Comprehensive Pain Management of North Florida,Gainesville, Florida, DIAGNOSIS AND MINIMALLY
† Deceased

The International Association for the Study of Pain (IASP) has de ned pain as
“an unpleasant sensory and emotional experience associated with actual or
potential tissue damage, or de ned in terms of such damage”. Donald Price in his
1999 book Psychological Mechanisms of Pain and Analgesia by IASP Press proposed
an alternative de nition, arguing that the IASP de nition does not emphasize the
experiential nature of pain. He holds that pain is a ‘somatic perception containing
(1) a bodily sensation with qualities like those reported during tissue-damaging
stimulation, (2) an experienced threat associated with this sensation, (3) a feeling
of unpleasantness or other negative emotion based on this experienced threat’.
In 1931, the French medical missionary, Dr. Albert Schweitzer wrote “Pain is a
more terrible lord of mankind than even death itself”. These words emphasize the
scope of total human su1ering due to pain which may dramatically a1ect a
person’s life/quality of life. Pain remains among one of the most debilitating
symptoms as well as one of the most common symptoms which patients report.
Blair Smith and Nicole Torrance have addressed the Epidemiology of Chronic
Pain as a chapter in the book, Systematic Reviews in Pain Research: Methodology
Re ned edited by Henry J. McQuay, Eija Kalso, and R. Andrew Moore and
published by IASP Press in 2008. They write that it seems that up to half of the
adult population su1ers from chronic pain as de ned by the broad IASP de nition
and that 10-20% experience chronic pain when measures of clinical signi cance
are added to the de nition. They further state that the incidence of chronic pain
(though diA cult to estimate) may be between 5% and 10% per year and is
associated with poor health-related quality of life in all studies that measured this
Numerous potential therapeutic targets exist which may modulate nociceptive
processing including: ion channels, TRP channels, ASIC channels, stretch-activated
channels, signaling molecules/casades (pERK, p38MAPK protein kinases),
neurotrophins (BDNF, GDNF, NGF) inDammatory mediators, cytokines, adhesion
molecules, immune cells/glia, neurotransmitters (SP, NK1, CCK), adrenergic
receptors, purinergic receptors, toll-like receptors, and glutamate receptors.
Furthermore, it is not uncommon that opposing anti-inDammatory processes may
exist for certain pro-inDammatory/pro-nociceptive processes (e.g., acetylation of
MKP-1 promotes the interaction of MKP-1 with its substrate p38 MAPK, which

results in dephosphorylation of p38 MAPK). However, some of these targets do not
have clinically available agents to speci cally enhance or inhibit their function
and even if these agents existed, clinicians would not know which agents to utilize
for a specific individual patient’s pain complaints.
Furthermore, analgesics, modalities, neuromodulation, and interventional
techniques, etc. should not be used “in a vacuum”, but rather optimally in
conjunction with physical medicine, behavioral medicine, and other techniques as
part of an interdisciplinary team approach. Additionally, it is conceivable that
some pain complaints in some patients may need therapies targeting peripheral,
spinal, as well as supraspinal mechanisms in efforts to fully address their issues.
Despite an explosion of basic science pain research, the translation of these
advances into tangible and clinically useful diagnostic and therapeutic measures
to identify and ameliorate various human painful conditions has lagged.
Unfortunately, despite valiant e1orts, too many people continue to exist with
horri c pain and su1ering, some who have been helped a little, and some who
have not been helped at all. The eld of Pain Medicine is still relatively in its
infancy, but continues to gradually mature. Thus, it was heartening to learn that
as we approach the tail end of the “decade of pain”; Elsevier is adding the book
“Current Therapy in Pain” to its critically acclaimed “Current Therapy” series.
Perhaps one of the best known books in this series is Conn’s Current Therapy,
which was initially published in 1943 and has been revised yearly since. After 65
years, Current Therapy in Pain has surfaced in efforts to deliver a source of current
information on the eld of pain medicine which will be updated reasonably
frequently. In keeping with the style of the series “Current Therapy in Pain” is
clinically oriented. However, in contrast to other Current Therapy texts, “Current
Therapy in Pain” does not present all chapters without references. Although I
initially set out with the intention to keep this format, which is seen in some
chapters, it became apparent that it would be challenging to have all the chapters
without references, largely due to the immaturity and dynamic nature of the eld
of pain medicine.
The text is organized to initially present background information on pain
–taxonomy, pathophysiology and assessment. Various treatment strategies for acute
pain are then presented. The next sections deal with a number of
conditions/syndromes/issues which are painful or may interface with pain. Section
IV is devoted to Pain in Special Populations. Finally, Sections VII through XIII deal
with treatment approaches to pain (pharmacologic, behavioral medicine, physical
medicine and rehabilitation, neuromodulation, complementary and alternative
medicine, neurosurgical, and interventional). The text, although notcomprehensive of all pain-relieving strategies, is felt to present a reasonable
representation of available therapeutic options which may help alleviate pain.
Furthermore, because of the dynamic nature of pain and the attempt to present
current information, it is not intended that all treatment strategies presented in the
text are “tried and true” therapies which have stood the test of time, but only that
they are or may be available options for certain circumstances, now or in the
It is hoped that the experts who contributed to this text have presented
information which may be helpful/educational to clinicians and/or patients and
that future editions continue to present current and useful information related to
the ever-changing field of pain medicine.

A c k n o w l e d g m e n t s
The editor would like to thank and acknowledge the enormous e orts of Pya
Seidner who helped to bring this project to fruition.
The editor would like to acknowledge and thank the Re ex Sympathetic
Dystrophy Association (RSDA) for the use of Dr. R. Norman Harden’s chapter which
was initially written for RSDA.
The editor would also like to acknowledge and thank Dr. Kevin W. Roberts,
Chairman of the Department of Anesthesiology for Albany Medical College, for his
continued support throughout this project./
I distinctly remember the moment, more than 25 years ago. It is frozen in my
memory as if it occurred yesterday. With eyes closed, my senses recall the dim
lighting, the squeaking of aged and rarely waxed tongue-and-groove ! ooring
underfoot, the musty smell of weathered paper, dried binding glue and dust. This
was the library in the teaching hospital that served as my “home away from
home” as a neophyte physician. And that was where I went to seek help when I
began to steadily encounter patients with pain problems. And there were, it
seemed, so many … yet, on whose behalf my attending physicians shrugged their
collective shoulders and skillfully redirected the stream of discussion to more
discernible pathology. There was no malice, just discomfort, and I discovered why.
No one knew anything. The library shelves were devoid of journals and texts on
the subject.
Fast forward to 2008, and there is such an outpouring of pain-related
literature, I have to purposefully block out my schedule every Friday afternoon to
peruse what comes across my desk just to keep up before the week ends. Sure, I
have learned that it’s okay to say “I don’t know”, but there will be no
shouldershrugging or avoidance of the subject when medical trainees ask me those di cult
questions about the most common problem experienced by people seeking medical
care: pain! But how can most clinicians—who have so many areas of medicine to
keep up on—also keep up on all the advances in pain assessment and
The answer lies between the covers of this well-written, comprehensive yet
pointedly practical text. In this new addition to the highly valued “Current
Therapy” series, Dr. Howard Smith has assembled many of the leading authorities
in this rapidly-evolving 8eld to do that all-important and sel! ess work: write a
book that really can, and will, help to improve peoples’ lives. Would that I could
have discovered such a gem when I went searching, way back in “the dark ages”
of the late 20th century!
PERRY G. FINE, MD, Professor of Anesthesiology, Pain
Research Center, University of Utah School of Medicine,
Salt Lake City, UtahTable of Contents
Chapter 1: The Taxonomy of Pain
Chapter 2: Pathophysiology of Pain
Chapter 3: Neuropathic Pain: is the Emperor Wearing Clothes?
Chapter 4: Assessment of Pain in Older Adults
Chapter 5: Assessment of Pain in the Nonverbal and/or Cognitively
Impaired Older Adult
Chapter 6: Neuropathic Pain—Definition, Identification, and
Implications for Research and Therapy
Chapter 7: Brain Imaging in Painful States: Experimental and Clinical
Chapter 8: Potential Documentation Tools for Opioid Therapy
Chapter 9: Perioperative Use of COX-2 Agents
Chapter 10: Patient-Controlled Analgesia
Chapter 11: Perioperative Epidural Analgesia
Chapter 12: Continuous Peripheral Nerve Catheter Techniques
Chapter 13: Interpleural Analgesia
IV: CHRONIC PAIN: CANCER PAINChapter 14: Cancer Pain Management
Chapter 15: Migraine Headaches
Chapter 16: Headaches Other than Migraine
Chapter 17: Orofacial Pain
Chapter 18: Neck Pain
Chapter 19: Shoulder Pain
Chapter 20: Elbow Pain
Chapter 21: Hand Pain
Chapter 22: Back Pain
Chapter 23: Hip Pain
Chapter 24: Knee Pain
Chapter 25: Foot Pain
Chapter 26: Thoracic Pain
Chapter 27: Abdominal Pain
Chapter 28: Genitourinary Pain Syndromes: Interstitial Cystitis, Chronic
Prostatitis, Pelvic Floor Dysfunction, and Related Disorders
Chapter 29: Pelvic Pain
Chapter 30: Female Perineal/Pelvic Pain: The Rehabilitation Approach
Chapter 31: Fibromyalgia Syndrome
Chapter 32: Osteoarthritis: Etiology, Pathogenesis, and Treatment
Chapter 33: Rheumatoid Arthritis
Chapter 34: Painful Diabetic Peripheral Neuropathy
Chapter 35: Trigeminal Neuralgia
Chapter 36: Postherpetic Neuralgia
Chapter 37: Post Amputation Pain Disorders
Chapter 38: Spinal Cord Injury
Chapter 39: Complex Regional Pain Syndrome: Treatment Approaches
Chapter 40: Complex Regional Pain Syndrome Pathophysiology
Chapter 41: Interdisciplinary Management For Complex Regional Pain
SyndromeChapter 42: Lumbar Spinal Stenosis: Current Therapy and Future
Chapter 43: Failed Back Surgery Syndrome
Chapter 44: Poststroke Pain
Chapter 45: Pain and Pain Management Related to Hiv Infection
Chapter 46: Sickle Cell Anemia
Chapter 47: Sacroiliac Joint Pain
Chapter 48: Pain and Sleep
Chapter 49: Pain in Children
Chapter 50: Painin the Elderly
Chapter 51: Pain in the Palliative Care Population
Chapter 52: Pain in the Substance Abuse Population
Chapter 53: A Mechanism-Based Approachto Pain Pharmacotherapy:
Targeting Pain Modalities for Optimal Treatment Efficacy
Chapter 54: Opioid Pharmacotherapy
Chapter 55: Opioids Issues
Chapter 56: Opioid Tolerance, Dependence, and Hyperalgesia
Chapter 57: Gastrointestinal Dysfunction with Opioid Use
Chapter 58: Acetaminophen
Chapter 59: Steroids
Chapter 60: Nonsteroidal Anti-Inflammatory Drugs and
Cyclooxygenase2 Inhibitors
Chapter 61: Antidepressants
Chapter 62: Antiepileptic Drugs
Chapter 63: Local Anesthetics
Chapter 64: Muscle Relaxants
Chapter 65: α2-Agonists
Chapter 66: Glutamate Receptor Antagonists
Chapter 67: Botulinum Toxins for the Treatment of PainChapter 68: Topical Analgesic Agents
Chapter 69: Tramadol
Chapter 70: Psychological Aspects of Pain
Chapter 71: Hypnotic Analgesia
Chapter 72: Cognitive Therapy for Chronic Pain
Chapter 73: Physical Medicine Approaches to Pain Management
Chapter 74: Transcutaneous Electrical Nerve Stimulation
Chapter 75: Spinal Cord Stimulation for the Treatment of Chronic
Intractable Pain
Chapter 76: Complementary and Alternative Medicine for Noncancer
Chapter 77: Neurosurgical Treatment of Pain
Chapter 78: Myofascial Trigger Points
Chapter 79: Epidural Steroid Injections
Chapter 80: Diagnosis and Treatment of Facet-Mediated Chronic Low
Back Pain
Chapter 81: Intra-Articular Injections
Chapter 82: Radiofrequency Treatment
Chapter 83: Cryoanalgesia for Chronic Pain
Chapter 84: Sympathetic Blockade
Chapter 85: Diagnosis and Minimally Invasive Treatment of Lumbar
Discogenic Pain
Chapter 86: Vertebroplasty and Kyphoplasty
Chapter 87: Epidural Adhesiolysis
Chapter 88: Spinal AnalgesiaChapter 89: Epidemiology of Complications in Interventional Pain


Chapter 1
Harold Merskey
Taxonomy is the theory and practice of classi cation. For an ideal classi cation,
each item to be considered should be independent of all other items so that it
stands in its own place in the classi cation. For example, if we wish to classify
peoples’ names for a telephone directory, each name must represent a separate and
distinguishable item. The classi cation must also be comprehensive (Box 1–1). If
two or more people have names such as John A. Smith, then an additional criterion
must be used to distinguish each John A. Smith and this can be done by adding a
street address. If there are two John A. Smiths, each with his own telephone
number at exactly the same address—most likely father and son, or if there are
three, grandfather, father, and son—they may use a numeric superscript or a
1 2 3numeric postscript as John A. Smith , John A. Smith , John A. Smith. That
provides a perfect classi cation useful for the purpose for which it is intended and
of little or no interest besides.
• Comprehensive
• Specific place for each item
Natural classi cations such as animal, vegetable, or mineral are more exciting
and even sometimes intellectually beautiful, for example, the periodic table in
chemistry. Nearly always (apart perhaps from some isotopes made by people) this
meets the highest standards of classi cation also. Each element has a place of its
own into which it ts and no other element with which it can be confused.
Evolutionary classi cations of ora and fauna similarly achieve great success,
although disputes may arise in marginal cases (Box 1–2).


Telephone directory
Medical classi cation lacks the rigor of either the telephone directory or the
periodic table. It is exceptionally untidy, but it is taken to re ect in some way “the
absolute truth” or at least the wonderful truth, as known to the best practitioners.
Accordingly, physicians endeavor to create true descriptions of individual “true”
disorders, each helping to some extent to improve upon the worth of the previous
ones. Classi cation may then be bedeviled by an argument about the criteria that
apply to a particular diagnosis, for example, what i s Cervicogenic Headache? What
i s the di7erence after an injury between that and Migraine if Migraine occurs with
photophobia or phonophobia and nausea? Are there two or more disorders, each
with its essential characteristics?
These disputes form an interesting adjunct to classi cation and may or may not
be illuminating, but resolving them is not part of the primary function of a
classi catory system. Classi cation is not a means of reaching an absolute truth but
rather a means of establishing ways to code data that can be shared and compared
between different practitioners or investigators.
The main task of the classi er is simply to make sure that individuals can
identify and locate types of objects or events. The classi er is not required to
1establish a true “meaning.” Thus, if physicians in di7erent parts of the world wish
to exchange information about headache, it is not necessarily important to resolve,
rst, whether Migraine should or should not include phonophobia in its
classi cation. Rather, it is important to identify headaches that are unilateral or
bilateral, and then whether photophobia, phonophobia, nausea, and vomiting
occur together with varying durations of the event. Thus, data can be collected for
comparison between di7erent groups with respect to the items used to identify
particular events, and any consequences that we wish to suppose follow from them,
such as loss of response to di7erent treatments and so forth. Of course, this does
mean that one has to have some sort of idea about which criteria one wishes to put
together in one classi catory slot and which criteria go into another classi catory
slot. We are not really interested in comparing cases of headache with cases of
elephantiasis. That separation is easily made. Separations between types of
headache become a topic for study within the framework of an overall definition.
It is just as well that classi cation can be used in the way just mentioned. Were
that not the case, we would be left with irreconcilable arguments and spend all our
time trying to determine whether all physical illnesses were hereditary and
secondary to psychological status, or whether some physical illnesses certainly were

due to environmental causes and others resulted from ill treatment in childhood.
A workable system of classi cation needs to proceed on the basis of information
that is largely agreed and to de ne areas of disagreement so that these can be
further explored. This is a reasonable way to avoid controversy about medical
diagnoses and to pursue knowledge.
Existing medical classi cations vary enormously but are all, or nearly all, illogical.
In the International Classi cation of Diseases and Related Health Problems, 10th
2edition (ICD-10), for example, we nd that conditions are classi ed by causal
agent (e.g., infectious diseases or neoplasms); by systems of the body (e.g.,
gastrointestinal or genitourinary); or by symptom pattern and type of psychiatric
illnesses (including a7ective psychosis, schizophrenic psychosis, organic psychoses,
depressive and anxiety disorders, and personality disorders) (Box 1–3).
By Cause
By Organ
By System
Parkinson’s Disease
By Site
Low back pain
By Symptom
All of the psychiatric conditions just mentioned, except for Personality Disorders,
are segregated into a category known in the American Psychiatric Association’s
Diagnostic and Statistical Manual of Mental Disorders in several editions (DSM-IV
3TR, at present ) as “Axis I Type Disorders,” and Personality Disorders are classi ed
in an additional axis (Axis II). Patients may have any number of disorders from

Axis I (e.g., Major Depressive Disorder plus Post-Traumatic Stress Disorder), and
another diagnosis as well on Axis II (e.g., 301.4 Obsessive Compulsive Personality
Disorder) (Box 1–4).
Rights were not granted to include this box in electronic media. Please refer to the
printed book.
From American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, 4th ed. (DSM-IV). Washington, DC: APA Press, 2000.
Medical diagnoses can also be classi ed by time of occurrence in relation to
stages of life, for instance, congenital anomalies, conditions originating in the
perinatal period, or presenile and senile disorders. At the lowest level of
classi cation, that is, the simplest and least complex description of phenomena,
conditions used to be classi ed simply as “Symptoms, Signs and Ill-De ned
Conditions” and are now classi ed as Symptoms and Signs, which actually
2constitute a group on their own in the ICD-10. Not only illness is classi ed in
4medical lists. There was also a code in ICD-9 : ICD650 for delivery in a completely
normal case of pregnancy. The nearest to this now appears in ICD-10 as Single
Spontaneous Delivery.
Within the major medical groups of ICD-9 and -10 and particularly the
neurologic section, there are subdivisions by symptom pattern (e.g., epilepsy or

migraine), by the presence of hereditary or degenerative disease (e.g., cerebral
degenerations that may be manifest in childhood or adult life), and by symptom
pattern (e.g., Parkinson’s disease, chorea, and types of cellular change).
Accordingly, there are also diagnoses by location (e.g., spinocerebellar disease)
and by infectious causes within the neurologic group (which is de ned rst by
location, e.g., meningitis).
If we look at pain disorders, there are codes in the ICD-10 for “Migraine” (G43)
and 9 subtypes, and separately for “Other Headache Syndromes” (G44) with 10
subcategories. There are codes for “Juvenile Ankylosing Spondylitis” (M081) and
for “Ankylosing Spondylitis in adults” (M45), as for “Seropositive Rheumatoid
Arthritis” (M05) with 6 subordinate categories and for “Other Rheumatoid
Arthritis” with 9 subordinate categories (M06). Among Symptoms and Signs, we
nd “Headache” (R51). In the Cardiologic section, R07 includes precordial pain in
the anterior chest wall (NOS); this may be pain in the musculoskeletal system or
refer to a neuralgic type of pain and precordial pain, which may well not be
cardiac. If we look at Endocrinology, we may simply diagnose “Diabetes,” which
was once one disorder but is now de ned in terms of 5 subtypes on a biochemical
and therapeutic basis. Among Musculoskeletal conditions, we have “Fibromyalgia”
de ned by a distribution of pain and tender points and not by what might be its
supposed innermost essence, and “Repetitive Strain Syndrome” is diagnosed,
whether rightly wrongly, on the basis of pain in parts that are overused.
To resolve some of the problems of comparing these illnesses, the American
5Psychiatric Association’s DSM-III provided at least ve di7erent Axes on which
conditions might be classi ed including Axis I: Clinical Disorders; Axis II:
Personality Disorders, Mental Retardation, or Speci c Development Disorders; Axis
III: General Medical Conditions; Axis IV: Psychosocial and Environmental
Problems; and Axis V: Global Assessment of Functioning. This system allows us to
classify both symptom patterns and people, an interesting conclusion, although the
classi cation of people is notoriously unreliable whether by psychiatrists or by
anyone else in the medical context.
To add to these hazards, we can also note that we may diagnose psychiatric
conditions from serology (e.g., genetics [e.g., Huntington’s chorea]), symptom
pattern (e.g., schizophrenia, depression, bipolar illness), reported mechanism (e.g.,
tension headache), and even the presence or the absence of irrational behavior
(e.g., psychosis vs. neurosis, although the latter term is not much used nowadays
and was dropped from DSM-III onward).
One of the obvious responses in a situation in which classi cation cannot be
provided on a theoretical basis is to provide agreed operational de nitions. This
brings us back to the starting point of this discussion at which it was pointed out
that only two things really matter in a classi cation system, one is a distinction

between A, B, and C and the other is that everything from A to Z will be included
that is part of the material to be classified.
Thus, it follows that even within medicine, the range of classificatory systems can
be enormous. There are highly specialized and valuable classi cations that will
6code the varieties and degrees of a single diagnostic category such as stroke, and
there are also classi cations that cover not just the type of illness or condition
examined but simply the reason for consultation. Thus, the ICCPC, the
7International Classi cation of Conditions in Primary Care does not classify
diseases but rather the reason for contact between the family practitioner and her
or his patient. Such a classi cation will include the reason for a patient being in the
doctor’s oP ce (e.g., advice on a symptom, review of treatment, completion of a
referral form, and completion of an insurance company form). All these items are
classi able and can be examined for whatever statistical purpose desired. The one
thing classi cation does not do is provide a statement of absolute truth about the
ultimate meaning of all medical disorders—or even one.
In 1983, citing others, it was said that, “There has long been a need for
1classi cation in the eld of pain.” A classi cation of pain was prepared originally
8for the International Association for the Study of Pain, and first published in 1986,
with a second edition in 1994. The aim of the classi cation is described in the
9introduction to the 1994 volume as being to classify the major causes of chronic
pain and to organize descriptions of the syndromes. It turned out slightly
At rst, it was not felt possible nor desirable to classify all painful conditions. A
good classi cation of pain was principally required for practitioners who were
specializing in the treatment of painful disorders and who needed to distinguish
them from other disorders and disabilities. Thus, it was inappropriate to include the
pain of appendicitis or tonsillectomy in a classi cation of chronic pain, but it was
desirable to have a systematic arrangement of conditions that commonly caused
chronic pain. Any attempt to do otherwise would, of course, have amounted to
writing an extensive textbook of medicine. The purpose of such a classi cation
would be to provide a means of communication between specialists in the eld of
pain, enable them to know that when one published a report on, for example,
sprain injuries, the same disorders would be at least broadly similar to that which a
di7erent person would call by the same name, even internationally. A few types of
acute pain were admitted to the classi cation for comparative purposes and
because they frequently gave rise to chronic pain (e.g., postherpetic neuralgia). The
Taxonomy of Chronic Pain, which was produced by the Task Force on Taxonomy
of the International Association for the Study of Pain (IASP), known as the Sub-


Committee, thus attempted to cover the major causes of chronic pain and some
illustrative examples of acute pain.
That being easily decided, the most diP cult problem was to determine the best
approach to organizing pain syndromes. It is obviously theoretically possible to
arrange pain syndromes by region of the body or by organ system (e.g., cardiac
pains, musculoskeletal pains, and pain due to neurologic illness, and so forth).
Alternatively, one might arrange pain syndromes by their purported causes (e.g.,
postherpetic neuralgia, which it is immediately obvious also could come under the
Neurologic rubric.
The Task Force on Taxonomy of the IASP decided, after some vigorous discussion,
that it would be unwise to classify on the basis of etiology. Etiology is the topic that
most concerns practitioners because we think that it leads us to make the most
useful diagnoses. Diagnosis is seen as the avenue to correct treatment. To give up
the idea that we can classify by etiology rst means recognizing that the empirical
methods of medicine are not yet good enough to provide etiologic classi cation, at
least in the field of pain.
An attempt was made by a group at the National Institutes for Dental Research
in the late 1970s to classify orofacial pain by etiology. The IASP subcommittee
concluded that, although the classi cation was detailed and well worked out, there
was insuP cient agreement on etiology to make that approach satisfactory for pain
as a whole. An impressive classification had actually been developed by the late Dr.
10John Bonica in his classic work, The Management of Pain. Bonica had started
with regions of the body and turned to diagnosis only after he had arranged the
subject by region. The committee was unanimous that the best way to start was by
region of the body because this was the least controversial and should be the rst
basis for classification.
The next step was to look at whether systems, patterns of pain, or etiology should
come next. Etiology again lost out. The system involved seemed to be the next
obvious agreed basis for arranging observations on pain. Not only was etiology
displaced from the rst position and the second position, but there was also
agreement that it should be left to the end to work out what we could best do about
it. Accordingly, the next part of the classi cation system focused upon the temporal
characteristics of pain and the pattern of occurrence for which coding was
provided. Everyone was comfortable after that in grading the pain according to its
intensity, and so, the rst four Axes of a pain classi cation had emerged as regions,
systems, temporal characteristics, and intensity combined with duration since
onset. Finally, room was left for etiology, and that was classi ed as genetic or
congenital: trauma; surgery; infective or parasitic; in ammatory but with no

known infective agent and immune reactions; neoplasm; toxic; metabolic;
degenerative; dysfunctional (including psychophysiologic); unknown or other; and
lastly, psychological origins. Each of these codings acquired a number from 0 to 9
(Box 1–5).
I. Site
II. System
III. Pattern of Pain
IV. Intensity and Duration of Pain
V. Etiology
8IASP, International Association for the Study of Pain.
As an example of how the coding system works, consider common migraine.
Migraine was coded 4 in the third Axis on the basis the pattern of occurrence being
one of recurring irregularly. A period is inserted for convenience of citing extra
numbers. Axis IV re ects the patient’s statement of intensity and time since the
onset of pain, so that a mild pain present for 1 month or less was coded at.1, and a
severe pain present for more than 6 months was coded at.9. Because this criterion
can vary from case to case within the same diagnostic category, the letter X was
placed to re ect the fourth Axis and to signify that each case would have its
features determined on the occasion of coding and not arbitrarily beforehand.
Code 7 concerning Migraine was a statement indicating modesty about
knowledge of the exact origins of the condition. Thus, the initially constructed code
for Common Migraine ran 004.X7. However, Classical Migraine also satis es these
criteria, and therefore, Classical Migraine was coded as 004.X7a and Common
Migraine was coded as 004.X7b.
A code of 0 is given for the head, face, and mouth; 0 for the nervous system,
whether central, peripheral autonomi,c or special senses.
As indicated, the X code symbol was used to permit the clinician to determine
the features of that particular case in accordance with whether the intensity was
mild, medium, or severe, and the duration was less than 1 month, between 1
month and 6 months, or more than 6 months. Thus, mild intensity of more than 6
months was rated as 3, medium intensity of more than 6 months was rated as 6,
severe intensity equal to or more than 1 month but less than 6 months was rated at
8, and so on.
Lastly as indicated, codes were given for etiology. Despite using ve places

organized at a default sequence of XXX.XX which in the case of common migraine,
as just discussed, was shown as 004.X7b, a number of classi cations could
theoretically use these additional codes. In order to discriminate between
conditions occupying the same ve Axis locations, additional letters were required,
namely a, b, c, and d, so that Classical and Common Migraine were coded as
0004.X7a and 004.X7b, respectively.
This system of coding by special characteristics is intended to allow comparisons
between groups of cases. To the best of my knowledge, it has not been used a lot in
clinical practice or in research investigations. However, a number of the diagnostic
categories have been popular, clinicians frequently referring to the descriptions and
characteristics provided for them. This particularly applies to bromyalgia and
complex regional pain syndrome, conditions in which there was more doubt about
the traditional appreciation of the disorder. The section on Back Pain is also used
by some. As well, occasional rare syndromes that appeared in the classi cation
were conveniently identi ed through it by members of the IASP who were able to
refer to relevant sections of the classi cation in order to assist a diagnosis. This was
noted, for example, with the fairly rare syndrome of painful legs and moving toes,
which sometimes also involves the arms and which is due to dorsal ganglion or
spinal cord damage. This is a condition that was on occasion previously treated as
The uses of classi cation are thus essentially pragmatic (Box 1–6). It is important
to understand that issues as to what a “real illness” is or what constitutes “a
genuine syndrome” are not easily solved and should not get in the way of the
diagnosis and treatment of patients. Rather, it is necessary to have a structured
method of characterizing syndromes, whether or not this describes their supposed
true essence or is in accordance with particular claims about etiology or
signi cance. Given the structured method, we can proceed to identify the
subordinate phenomena that may lead to a more re ned diagnosis. Even when
there is a re ned diagnosis, it still may not be something that can be called an
absolute truth but rather a step on the way to improved management, which is
what clinical medicine is actually about. Such a modest aim nevertheless does not
inhibit clinical description from proceeding to more fundamental analyses by
interested scientists who may or may not be the clinicians.
Uniform standards of diagnosisStatistical
Service delivery
Billing and planning
1. Merskey H. Development of a universal language of pain syndromes. In: Bonica JJ,
editor. Advances in Pain Research and Therapy, 5. New York: Raven; 1983:37-52.
2. World Health Organization. International Classification of Diseases and Related
Health Problems. Geneva: WHO, 1992. 10th rev. (ICD-10)
3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, 4th. Washington, DC: APA Press, 2000. (DSM-IV)
4. World Health Organization. International Classification of Diseases and Related
Health Problems. Geneva: WHO, 1978. 9th rev. (ICD-9)
5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders, 3rd. Washington, DC: APA Press, 1980. (DSM-III)
6. Capildeo R, Haberman S, Rose FC. New classification of stroke. Preliminary
communication. Br Med J. 1977;2:1578-1580.
7. Lamberts H, Wood M. International Classification of Primary Care. Oxford: Oxford
University Press, 1989. (Reprinted with corrections, 1989.)
8. Merskey H (ed): Classification of chronic pain: descriptions of chronic pain
syndromes and definitions of pain terms. Monograph for the Sub-Committee on
Taxonomy, International Association for the Study of Pain. Pain (suppl 3).
Amsterdam: Elsevier Science, 1986.
9. Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and
Definitions of Pain Terms,. Merskey H, Bogduk N, editors. 2nd. Seattle: IASP
Press, 1994.
10. Bonica JJ. The Management of Pain. Philadelphia: Lippincott, 1953.


Chapter 2
Jun-Ming Zhang, Mark L. Baccei
Pain is de ned as “an unpleasant sensory and emotional experience associated with
actual or potential tissue damage, or described in terms of such damage.” Under
normal physiologic conditions, pain is elicited by the activation of speci c
nociceptors (nociceptive pain). However, it may also result from a lesion or
dysfunction of peripheral a erent bers or the central nervous system (CNS) itself
(neuropathic pain). Although acute nociceptive pain serves as a warning signal
regarding possible severe tissue damage, chronic and/or neuropathic pain is
persistent and maladaptive.
Pain involves sensory, emotional, and cognitive components. Although it may be
classi ed in many ways, pain can often be categorized as nociceptive, neuropathic,
mixed, or idiopathic pain.
Nociceptive Pain
Pain is termed nociceptive when the clinical evaluation suggests that it is sustained
primarily by the nociceptive system. Nociceptive pain is pain that is proportionate
to the degree of actual tissue damage. A more severe injury results in a pain that is
perceived to be greater than that caused by a less severe injury. Such pain serves a
protective function. Sensing a noxious stimulus, a person behaves in certain ways
to reduce the injury and promote healing (e.g., pulling his or her nger away from
a hot object). This “good” pain serves a positive function. Examples of nociceptive
pain include acute burns, bone fracture, and other somatic and visceral pains.
Neuropathic Pain
Unlike nociceptive pain, neuropathic pain occurs through peripheral nervous
system (PNS) changes, such as neuroma formation, generation of ectopic discharge
from the injured axons or the somata of the dorsal root ganglion (DRG) neurons, or
through CNS changes that can lead to enhanced excitability of central pain
networks (termed central sensitization) in patients with a prolonged exposure to

noxious stimuli or nerve injury. It is disproportionate to the degree of tissue damage
and can also persist in the absence of continued noxious stimulation (i.e., the
pathophysiologic changes become independent of the inciting event). Thus,
neuropathic pain serves no protective function and provides no bene t to the
overall health of the person. The underlying causes of neuropathic pain are
discussed in a later section (Table 2–1).
Table 2–1 Comparison of “Good” Pain and “Bad” Pain
Nociceptive Pain Neuropathic Pain
• Warns of acute or potential damage • Pain caused by nerve injury
• Protective function • Spontaneous, evoked activity
• Can be differentiated from touch • Develops in days or months
• Transient • Associated with inflammation,
• Well localized
• Associated with peripheral and central
• C- and Aδ-fiber–mediated sensitization
• Increased activity, wide dynamic • Pain outlasts duration of the stimulus
range neurons
• Pain sensed in noninjured areas
• Opioid sensitive
• Elicited by Aβ (?) as well as C and Aδ
• Opioid insensitive
Mixed Pain
In a given patient, components of continued nociceptive pain may coexist with a
component of neuropathic pain. Patients with persistent back and leg pain after
lumbar spine surgery (failed low back surgery syndrome) represent a common
example. Some patients with complex regional pain syndrome (CRPS; re ex
sympathetic dystrophy or causalgia) may develop painful complications that are
nociceptive (e.g., joint ankylosis, myofascial pain) and that coexist with the
underlying neuropathic pain.
Idiopathic Pain
Idiopathic pain may be de ned as pain that persists without any identi able





organic lesions or that is disproportionate to the degree of tissue damage.
Understanding the pathophysiology of abnormal or nonphysiologic pain requires
basic knowledge of the pathways mediating the perception of somatosensory
stimuli under normal conditions. The rst step in this process involves the
transduction of the sensory stimulus (which can be mechanical, thermal, or
chemical) into an electrical potential by rst-order a erent neurons in the DRG
located external to the spinal cord. These neurons express specialized receptors at
their distal ends that respond to speci c types of external (e.g., the skin) or internal
(e.g., visceral organs such as the liver) sensory stimuli by opening ion channels in
their membrane. This results in a depolarization of the sensory neuron, which can
trigger the generation of an action potential that propagates to the dorsal horn of
the spinal cord. It is now clear that the size of the sensory neuron can provide
signi cant clues as to its function. Large-diameter DRG neurons possess large
myelinated axons with rapid conduction velocities in the Aβ range (>30 m/sec)
and generally transmit information about innocuous mechanosensation (e.g.,
touch, vibration). Noxious stimulation is transmitted via small-diameter DRG
neurons that give rise to either thin myelinated Aδ bers (which conduct impulses
at 2–30 m/sec) or small unmyelinated C-fibers (with conduction velocities of
The signals carried by all three types of sensory a erents are integrated by the
synaptic network within the spinal dorsal horn, which consists of both local circuit
interneurons and second-order projection neurons that transmit impulses from the
spinal cord to higher brain areas (including the thalamus) predominantly via the
spinothalamic tract (STT). The output of these STT neurons depends on the net
balance between inhibitory and facilitatory mechanisms within the dorsal horn. For
example, repetitive stimulation of tactile Aβ mechanoreceptive inputs can activate
spinal interneurons and inhibit the response of STT neurons by decreasing the
amount of glutamate released from the presynaptic terminals of nociceptive
Cbers in the dorsal horn. This is believed to underlie the e ectiveness of both
transcutaneous electrical nerve stimulation (TENS) and dorsal column stimulation
as clinically therapeutic interventions for patients with pain. In contrast, responses
of STT neurons to nociceptive stimuli can be facilitated if they have been subjected
to long-term excessive input from C- ber nociceptive neurons (sensitization), which
can be caused by chronic in ammation or other chronic noxious stimulation of
Cbers. The excitability of STT neurons is also modulated by descending projections
to the spinal cord from higher areas of the CNS (such as the rostral medulla), which
can cause both facilitation and inhibition under different conditions.
The activation of third-order neurons in the thalamus by STT inputs allows the
transmission of the noxious information to the cerebral cortex, where theperception of pain is generated. Evidence exists that numerous supraspinal control
areas—including the reticular formation, midbrain, thalamus, hypothalamus, the
limbic system of the amygdala and the cingulate cortex, basal ganglia, and
cerebral cortex—modulate the sensation of pain (Table 2–2).
Table 2–2 Spinocerebral Ascending Pathways
Spinothalamic Crosses the midline and ascends on the opposite side of
pathway the spinal cord to the ventral posterolateral nucleus of
the thalamus. This nucleus is subdivided for specific
areas of the body, and each area projects to its own
section of the primary sensory cortex—a thin band of
cortex in the parietal lobe just posterior to the central
sulcus. This discriminative pathway transmits to
consciousness precise information about the location of
Spinoreticular Ascends on both sides of the spinal cord to the
pathway intralaminar nuclei of both the right and the left
thalamus. From there, the next neuron in the chain takes
the information to many areas of the brain—e.g., the
anterior part of the cingulate gyrus (emotion), the
amygdala (memory and emotion), and the
hypothalamus (emotion and the vascular response to
Dorsal column Transmits visceral nociception (as well as somatic touch
pathway and position sense) to the thalamus.
Spinomesencephalic Travels with the spinotectal tract to the periaqueductal
tract gray matter and superior colliculus of the midbrain. This
may be the same as, or related to, the pathway traveling
to the parabrachial nucleus in the brainstem—which in
turn projects to the amygdala, hypothalamus, and other
limbic system structures in the forebrain.
Spinohypothalamic A recently described route; does not synapse in the
pathway reticular formation. It carries information of emotional
significance from the skin, lips, sex organs,
gastrointestinal tract, intracranial blood vessels, tongue,
and cornea directly to the hypothalamus.=
Pathologic pain occurs when prolonged nociception continues to drive pain that
outlasts its physiologic usefulness (as a signal to avoid harm and promote healing)
and when pain-processing mechanisms themselves function abnormally. The latter
occurs in neuropathic pain syndromes, such as postherpetic neuralgia and central
pain due to stroke (Table 2–3). The mechanisms underlying neuropathic pain
involve both peripheral and central components. Although a comprehensive
summary of the changes that occur in the nervous system after peripheral nerve
injury is outside the scope of the present chapter, we highlight some key
mechanisms later.
Table 2–3 Clinical Causes of Neuropathic Pain
Nerve injury
• Nerve compression (entrapment
neuropathies, tumors)
• Nerve crush, stretching, incomplete
transection (trauma)
• Neuropathy (diabetes, irradiation, ischemia,
• Neuroma (amputation, nerve transection)
Dorsal root ganglion
• Compression (disk, tumor, scar tissue)
• Root avulsion
• Inflammation (postherpetic neuralgia)
Spinal cord, brainstem,
• Spinal cord, brainstem, thalamus, cortexthalamus, cortex
• Infarction, tumors, trauma
Peripheral Mechanisms
Altered Expression of Ion Channels in Axotomized Sensory Neurons
Spontaneous activity originating from the somata is rarely observed in DRG cells
1with normal, uninjured axons. However, this is a common phenomenon after the
peripheral axons are injured and re ects underlying alterations in the complement
2-10of voltage-gated ion channels expressed by DRG neurons. There is now

compelling evidence that the expression of sodium channel subtypes (e.g., Na 1.3,v
Na 1.7, Na 1.8, and Na 1.9) is dramatically altered by nerve injury and mayv v v
account for the increased excitability of neuropathic DRG neurons in models of
11-13chronic pain. The accumulation of Na 1.3 channels in the injured DRGv
somata and neuroma may play a signi cant role in the development and
maintenance of ectopic discharges. Meanwhile, the loss of sodium currents
mediated by the Na 1.8, and Na 1.9 subtypes in injured DRG neurons leads to av v
hyperpolarization of the resting membrane potential. Paradoxically, this may
contribute to the enhanced excitability of these neurons by relieving the
steady+state inactivation of other Na channel subtypes (such as Na 1.3), thus increasingv
+the size of overall Na influx and the likelihood of action potential discharge.
A reduction in the density of potassium channels (or an alteration in their
functional properties) after axotomy may also increase the excitability of sensory
+neurons. Indeed, it has been shown that K conductance is decreased signi cantly
in nerve-injured DRG cells. This is also supported by observations that mexiletine,
+which can lead to an attenuation of neuropathic pain, also facilitates K currents
in DRG neurons.
Previous work has also demonstrated that peripheral nerve injury causes
2+alterations in the expression of voltage-sensitive Ca channels in DRG neurons.
Because these channels (particularly N-type) are involved in controlling the release
of neurotransmitters from the terminals of sensory, central, and sympathetic
neurons in the spinal cord, these alterations have signi cant implications for
nociceptive processing under pathologic conditions. In fact, the ability of
anticonvulsants (carbemazepine and gabapentin) to reduce mechanical allodynia
(both in the clinic and in experimental models of neuropathic pain) may involve,
2+among other mechanisms, an interaction with Ca channels localized on the
injured DRG neurons.
Sympathetic Excitation of Injured Sensory Neurons
CRPS II (causalgia) is a classic example of sympathetically maintained pain (SMP)
associated with PNS injury. It is characterized by a distal burning sensation that is
14exacerbated by cold and gentle mechanical stimulation. Clinically, SMP appears
to be a signi cant component of various painful conditions such as CRPS, phantom
pain, neuralgias, and herpes zoster. Clinical observations and animal studies have
shown that coupling of the activated sympathetic nervous system and the sensitized
sensory nervous system is important for development of SMP. Under normal
physiologic conditions, the a erent sensory nervous system and the e erent
sympathetic nervous system are anatomically separated and functionally
independent of each other. There is evidence, however, that an abnormally



enhanced communication between these two systems may occur under pathologic
conditions. For example, sympathetic stimulation may excite sensory neurons in
animals with in amed peripheral tissue or after peripheral nerve injury. Chemical
or surgical sympathectomy may relieve allodynia and hyperalgesia and improve
chronic pain behavior. These observations suggest that increased activity of the
sympathetic nervous system may be involved in the sensitization of sensory neurons
toward the development of neuropathic pain.
Sympathetic-sensory coupling may occur either centrally or peripherally. The
DRG has been identi ed as an important site for peripheral sympathetic-sensory
coupling. Within the normal DRG, sympathetic axons are only found
accompanying blood vessels. After peripheral nerve injury, sympathetic e erent
bers extensively sprout into both DRG and spinal nerves. Sprouting bers
sometime form distinctive basket-like webs (sympathetic baskets) or rings wrapping
15around medium and large DRG neurons. Although it is currently unclear what
16triggers the sprouting of sympathetic nerve bers in the ganglia, recent studies
suggest that sympathetic sprouting is associated with the in ammatory responses
within the axotomized DRG and may be mediated by abnormal spontaneous
activity of the DRG neurons.
Inflammatory Cytokines and Chemokines
Proin ammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin
(IL)-1 and IL-6, and chemokines (e.g., monocyte chemoattractant protein-1
[MCP1]) may be produced in and by peripheral nerve tissue during physiologic and
pathologic processes by resident and recruited macrophages, mast cells, endothelial
cells, Schwann cells, and neurons. After PNS injury, macrophages and Schwann
cells that gather around the nerve injury site secrete cytokines and speci c growth
factors required for nerve regeneration. The cytokines may be synthesized in the
DRG or may be transported in a retrograde fashion from the periphery, via axonal
or nonaxonal mechanisms, to the DRG and dorsal horn of the spinal cord, where
they can have profound effects on neuronal activity and pain sensitivity.
Spinal Mechanisms: Central Sensitization
After peripheral nerve injury, strong activation of nociceptive afferents, particularly
C- ber nociceptors, may lead to sensitization of dorsal horn neurons (i.e., “central
17sensitization”). This can result in the following alterations in the physiologic
properties of dorsal horn neurons: (1) increased size of the receptive eld (i.e., the
area of the body that, when stimulated, evokes action potential ring in the cell);
(2) lower thresholds; neurons begin to re in response to low-threshold a erent
inputs that were previously too weak to evoke action potential discharge; (3)
increased magnitude of action potential discharge in response to nociceptive

inputs; and (4) increased spontaneous impulse activity. These alterations are
believed to signi cantly contribute to the hyperalgesia, allodynia, and spontaneous
pain that result from peripheral nerve injury. As a result, the mechanisms
underlying central sensitization have been intensely studied, and the most relevant
findings are briefly summarized later.
Long-term Potentiation of Nociceptive Inputs in the Dorsal Horn
The repetitive activation of high-threshold C- bers (as might occur at the time of a
peripheral nerve injury) can result in a prolonged increase in the strength of their
synaptic connections with dorsal horn neurons. The result is that a given impulse
traveling along the nociceptive ber can produce a greater depolarization of the
second-order neurons in the spinal cord. This may re ect the insertion of additional
glutamate receptors at the postsynaptic site or by altering the function of receptors
that already exist at the synapse. Importantly, in lamina I of the dorsal horn, this
potentiation of synaptic eR cacy occurs selectively on spinal projection neurons
(i.e., the output cells of the dorsal horn). Thus, strong activation of nociceptive
sensory a erents can lead to a greater synaptic drive onto spinal projection neurons
and a subsequent facilitation of pain transmission from the spinal cord to the brain.
Additional work has demonstrated that the activation of the
N-methyl-Daspartate (NMDA) subtype of glutamate receptor is necessary to induce long-term
potentiation (LTP) at nociceptive synapses in the super cial dorsal horn. Within
lamina I of the spinal cord, the activation of the substance P receptor (NK1) is also
required. Both of these receptors likely contribute to LTP by elevating the levels of
intracellular calcium in the dorsal horn neuron and thus activating downstream
signaling cascades involving protein kinases. Animal studies have con rmed that
both NMDA and NK1 receptors are involved in the induction and maintenance of
the central sensitization produced by high-threshold nociceptive a erent inputs at
the behavioral level. Because central sensitization is likely to contribute to the
18postinjury pain hypersensitivity states in humans, these data have a bearing on
the potential importance of NMDA and NK1 antagonists for preemptive analgesia
and the treatment of established pain states. However, it should be noted that other
types of receptors (e.g., metabotropic glutamate receptors, TrkB receptors) are also
capable of inducing synaptic plasticity in the dorsal horn.
Loss of Central Inhibition
Much attention has been given to the possibility that the hyperexcitability of spinal
neurons after nerve injury re ects a loss of synaptic inhibition in the dorsal horn.
This has emerged from previous experiments showing that the blockade of spinal
γaminobutyric acid receptor (GABA R) and glycine receptor (GlyR) (the two majorA A
inhibitory neurotransmitter receptors in the spinal cord) mimics the signs of central
sensitization. More recent studies have shown that such a reduction in inhibitory!


strength can indeed occur in the dorsal horn through a variety of mechanisms.
For example, peripheral nerve injury induces a marked reduction in the
amplitude of GABA R-mediated synaptic currents in super cial dorsal hornA
neurons and a corresponding increase in the fraction of cells that receive no
GABAergic input at all. This is accompanied by a reduction in the expression of the
GAD65 enzyme, which is largely responsible for the synthesis of GABA in the dorsal
horn. These changes are believed to result from the selective death of GABAergic
interneurons in the region after nerve damage, but the mechanisms underlying this
cell death are not yet clear.
The inhibition of neuronal excitability that normally results from the activation
–of GABA R and GlyR re ects the in ux of Cl across the cell membrane. TheA
–magnitude (and direction) of this ow depends on the relative concentration of Cl
inside versus outside the neuron. Recent work has shown that sciatic nerve injury
–leads to a decrease in the expression of the Cl transporter KCC2 (which serves to
–pump Cl out of the cell) in dorsal horn neurons and a subsequent build-up in the
–concentration of intracellular Cl , thereby reducing the electrochemical force
– –normally driving the Cl ions into the cell. Thus, after nerve injury, less Cl enters
the cell through an open GABA R (or GlyR), which translates into weaker synapticA
Under normal conditions, the production of pain from the activation of
nociceptors with mechanical stimuli is inhibited in the spinal dorsal horn by the
concurrent activation of Aβ mechanoreceptive a erents. This occurs in large part
through the activation of inhibitory spinal interneurons by Aβ sensory bers.
However, given the previously discussed reductions in the eR cacy of GABAergic
and glycinergic transmission, this mechanism will be much less e ective after
peripheral nerve injury, allowing for greater ring in the STT output cells in the
spinal cord. This likely contributes to the allodynia/hyperalgesia in patients with
peripheral nerve damage.
Spinal Glial Activation
There is now signi cant evidence showing that glial activation in the spinal cord
appears to be important for both the initiation and the maintenance of pathologic
pain. Astrocytes and microglia are activated by neuronal signals including
substance P, glutamate, and fractalkine. Fractalkine is a chemotactic cytokine
(chemokine) that is constitutively expressed in the nervous system where it is
tethered to the extracellular membrane surface of primary a erent neurons in an
inactive form via a mucin stalk. After nerve insult, the mucin stalk breaks, releasing
fractalkine in an active state, which is then free to bind to the CX3C receptor-1
(CX3CR-1) on glia, resulting in glial activation. Activation of glia by these!


substances leads to the release of mediators that then may act on other glia and
spinal neurons. These include proin ammatory cytokines (IL-1β), TNF-α, IL-6,
adenosine triphosphate (ATP), nitric oxide, and excitatory amino acids released
from microglia and astrocytes. These cytokines have been shown to be critical
mediators of allodynia.
Evidence also points to a role for spinal microglia in the weakening of GABAergic
inhibition that is observed after nerve injury. Activation of microglia with ATP
results in the release of brain-derived neurotrophic factor (BDNF) from these cells.
The subsequent binding of BDNF to its receptor TrkB localized on dorsal horn
–neurons causes an increase in the intracellular Cl concentration and a subsequent
decrease in the eR cacy of GABAergic inhibition, as described earlier. Importantly,
blocking BDNF release from microglia prevented both the reduction in GABAergic
strength and the development of mechanical hypersensitivity after nerve injury,
suggesting that targeting the glia-neuron signaling pathway may prove to be an
effective strategy for treating neuropathic pain.
Supraspinal Mechanisms: Pain Modulation
Descending connections between higher brain centers and the spinal cord can
either amplify or inhibit the transmission of pain-related signals. Mounting
evidence suggests that these descending systems are involved in the maintenance of
neuropathic pain. Injections of the local anesthetic lidocaine into the rostral
ventromedial medulla (RVM) given 6 to 12 days after a nerve injury abolished the
observed tactile and thermal hypersensitivity. A similar e ect was seen if the
dorsolateral funiculus, the main pathway from the RVM to the dorsal horn, was
lesioned prior to the nerve injury. These e ects suggest that peripheral nerve injury
results in the strengthening of the descending facilitatory pathways from the RVM,
producing an enhanced excitability of the dorsal horn and a subsequent increase in
the sensitivity to pain
The enhanced descending facilitation after nerve injury may re ect increased
19activation of “ON” cells in the RVM. As rst described by Fields, this subtype of
neuron in the RVM increases its rate of action potential ring immediately before
the tail- ick in response to a heat stimulus and may increase the transmission of
pain-related information to the brain. In contrast, a second group of neurons in the
RVM (the “OFF” cells) reduce their spontaneous ring rate immediately prior to the
rat’s moving its tail away from a noxious heat stimulus and is believed to inhibit
the transmission of pain-related information to the brain. A better understanding of
the interaction between the brainstem and the spinal cord after peripheral nerve
injury will greatly aid efforts to treat neuropathic pain.
Understanding the pathophysiology of pain requires knowledge of the underlying
neuronal plasticity at the levels of the nociceptive neurons, spinal cord, and brain.
Modulatory e ects at the nociceptor, sympathetically mediated pain, central
sensitization, and alterations in ascending/descending CNS pathways are all
involved in the perception of pain as well as the related pain motivations and
behaviors. Despite great advances in unraveling the complexities of the
pathophysiology of pain, much remains to be discovered that will hopefully lead to
better therapies.
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Chapter 3
Steven H. Horowitz
Current concepts of acute and chronic pain disorders distinguish “nociceptive,”
1“in ammatory,” “functional,” and “neuropathic” pains. Nociceptive pain is the
most common pain experienced when pain receptors (nociceptors) are activated, as
in tissue injury. In ammatory pain also involves nociceptor activation as a
consequence of in ammation. Transduction, conduction, and transmission of
nociceptor activity to conscious awareness involves peripheral and central nervous
system pain pathways that, when intact, function in a protective and adaptive
1manner. Damage to, or dysfunction of, these pain (somatosensory) pathways,
peripherally or centrally, can result in a di erent, less frequent, but nevertheless
important pain picture—that of neuropathic pain. Neuropathic pain confers no
functional bene t and may be considered a “maladaptive” response of the nervous
1system to the primary pathology.
After earlier periods of debate and uncertainty, the International Association for
the Study of Pain (IASP), in 1986 and then in 1994, sought to codify the concept of
neuropathic pain as “pain initiated or caused by a primary lesion or dysfunction of
2the nervous system.” Spirited attacks arose thereafter and have continued
unabated, mostly over the terms “lesion” and “dysfunction.” The de nition has
been considered narrow if the pain relates to a lesion and broad if it relates to
3dysfunction. Either way, it presupposes a demonstrable abnormality exclusive to
4the nervous system; not the result of ongoing tissue injury elsewhere. It is the word
“demonstrable” that is operative in this chapter.
The de nition also presupposes underlying pathophysiologic mechanisms
a ecting somatosensory components that are responsible for this special type of
pain and are common to multiple nervous system disorders. It further assumes,
given the limitations of human experimentation, that animal models are reasonable
correlates of the human pain condition and pain mechanisms discovered therein
5-7have clinical relevance (with exceptions). Such mechanisms include
spontaneous and ectopic a erent discharges, alterations in ion channel expression,
peripheral collateral sprouting of a erent neurons, sprouting of sympathetic
neurons into dorsal root ganglia, nociceptor sensitization, recruitment of silent'

nociceptors, dorsal horn dea erentation, central sensitization with changes in
receptive eld properties, decreased descending inhibition, and cerebral cortical
1,5-10reorganization, among others.
The disorders associated with neuropathic pain include polyneuropathies such as
those secondary to diabetes mellitus, alcoholism, and amyloidosis; idiopathic small
ber neuropathy; hereditary neuropathies; mononeuropathies, or neuronopathies
such as trigeminal, glossopharyngeal, and postherpetic neuralgias; entrapment
neuropathies; and traumatic nerve injuries producing complex regional pain
syndrome (CRPS) type II. CRPS type I is also considered a neuropathic pain
disorder, although evidence for nerve damage and/or dysfunction is more
controversial. Neuropathic pain can occur in central nervous system conditions,
especially spinal cord injury, multiple sclerosis, and cerebrovascular lesions
involving the brainstem and thalamus.
In reality, the diagnosis of neuropathic pain is often problematic. Clinically, a
distinction between nociceptive, in ammatory, and neuropathic pains is not
precise, and conditions such as diabetes mellitus, cancer, and neurologic diseases
with dystonia or spasticity can produce mixed pain pictures suggestive of multiple
8pathophysiologic mechanisms. As with other pains, the perception of neuropathic
pain is purely subjective, not easily described nor directly measured. Also, pain
pathway responses to damage are not static, but dynamic; signs and symptoms
change with pathway activation and responsiveness and with chronicity. Further,
the multiplicity of disorders that have neuropathic pain as a component of their
clinical presentations makes a single underlying pain mechanism unlikely. More
than one type of pain, and therefore, very likely more than one mechanism, may
occur in a single patient, and the same symptoms can be caused by disparate
8-10mechanisms. For these and other reasons, including the failure of
etiologybased or anatomy-based classi cations to be therapeutically helpful, a mechanistic
1approach to neuropathic pain management is currently advocated. Ideally,
speci c mechanisms or combinations of mechanisms would relate to speci c signs
and symptoms (speci c somatosensory phenotypes) and, ultimately, speci c
11therapies. Unfortunately, no objective methods of diagnosing underlying pain
12mechanisms exist at present. Should such methods be developed, diseases-based
symptom palliation strategies can be supplemented with “targeted”
mechanism13specific pharmacologic management.
Despite these complexities, there are several features to the clinical presentation of
neuropathic pain that support its diagnosis and should be sought during history
taking. In the case of mononeuropathies secondary to trauma, the severity of the$


pain often exceeds the severity of the inciting injury and the pain extends past the
healing period. CRPS can follow minor skin or joint trauma, bone fractures, or
injections. The pain is stimulus-independent and described as “burning,”
“lancinating,” “electric shock–like,” “jabbing,” and/or “cramping”; it is often
accompanied by pins-and-needles sensations and sometimes by intractable itching
(positive symptoms). These symptoms do not adhere to speci c peripheral nerve
distributions and often begin and remain most pronounced distally. The pain may
be worse at night when activity ceases and/or during cold, damp weather, and it is
exacerbated by movement of the a ected limb. Multiple types of pain (constant
pain with paroxysms and stimulus-evoked pains) can be experienced
simultaneously. It is useful to separate stimulus-independent and stimulus-evoked
6,9pains to di erentiate ongoing from provoked activities. Spread of symptoms
outside the initial site of injury is common; in the case of unilateral pain, there may
be spread to homologous sites in the opposite limb (mirror pain). Positive and
negative (numbness, loss of sensation) symptoms can occur concurrently,
sometimes accompanied by autonomic symptoms. Spontaneous pain, often without
complaints of sensory loss, is a feature of the cranial mononeuralgias—trigeminal,
glossopharyngeal, and postherpetic. Of course, location, intensity, and duration of
pain are extremely important.
In generalized polyneuropathies, rapid progression solely a ecting sensory bers
is more likely to be painful, especially if in ammation and ischemia are prominent,
8as in the vasculitidies. In painful polyneuropathies, for example, idiopathic small
ber neuropathy and diabetic polyneuropathy with predominant small ber
(Aδand C- bers) damage, the burning, lancinating, jabbing pains with
pins-andneedles sensations are nerve-length–dependent and bilaterally symmetrical,
beginning distally in the feet. Over time, symptoms ascend more proximally in the
lower extremities and may eventually a ect the hands. This centripetal progression
also occurs in intercostal nerve distributions, beginning anteriorly over the midline
of the torso with later symmetrical lateral extension to the anks. In patients with
14painful polyneuropathies, Otto and coworkers found that 88% complained of
deep aching pain, 86% of paresthesias, 69% pain on pressure (as when walking),
and 59% of paroxysmal pain. Autonomic complaints, for example, abnormal
sweating, impotence, orthostatic hypotension, and gastrointestinal and bladder
symptoms, are frequent.
Among the more common and important clinical signs in neuropathic pain
disorders are positive sensations—stimulus-evoked hypersensitivities such as
allodynia to innocuous stimuli (e.g., light touch and cold) and hyperalgesia to
noxious stimuli (e.g., pinprick). They occur focally in mononeuropathies and'

distally and symmetrically in polyneuropathies. Various forms of hyperalgesia
include touch-evoked (or static) mechanical hyperalgesia to gentle pressure,
pinprick hyperalgesia, blunt-pressure hyperalgesia, and punctate hyperalgesia that
8,9increases with repetitive stimulation (windup-like pain). Paradoxically, these
hypersensitivities can occur in areas in which the patient also complains of and
demonstrates loss of sensation. Persistence of stimulus-evoked pain after stimulus
withdrawal (aftersensation) can occur in the same anatomic distributions. As with
symptoms, spread of allodynia and hyperalgesia outside the original site of injury is
common and may extend to homologous sites in the opposite limb. Focal
autonomic abnormalities after nerve injury, especially of sweating, skin
temperature, and skin color, in conjunction with the aforementioned pain, ful ll
the diagnostic criteria of CRPS (discussed below). With chronicity, trophic changes
of the skin and nails may develop, as well as motor signs such as weakness, tremor,
and dystonia. Nerve percussion at points of compression, entrapment, or irritation
can elicit pins-and-needles or “electrical” sensations (Tinel’s sign) in the territory of
the nerve percussed.
In small ber neuropathies, de cits occur in thermal and pain perceptions and
sometimes touch, whereas large ber functions (e.g., muscle strength, re exes, and
perception of vibratory and proprioceptive stimuli) are normal. In combined large
and small ber polyneuropathies, all these functions are compromised. Symmetrical
distal autonomic dysfunction is often present but rarely severe.
In patients with signi cant neuropathic pain, clinical neurologic de cits are
demonstrable in many conditions, but not in others, for example, trigeminal and
glossopharyngeal neuralgias and, more than occasionally, postherpetic neuralgia.
Patients with small ber mono- or polyneuropathies, despite describing typical
neuropathic pain symptoms, may have normal examinations. There is the
temptation to attribute their pain complaints to functional or psychogenic causes;
however, at least from a logical perspective, that cannot always be the case, and if
they are known to have a particular disease such as diabetes or su ered an injury
in which nerve damage is likely, pain may be their only manifestation of neural
dysfunction. In such situations and in cases in which further diagnostic information
would be helpful, ancillary testing can be employed.
Any consideration of the utility of ancillary tests to support the diagnosis of speci c
neuropathic pain mechanisms must take into account several factors:
1. Currently, available tests only evaluate nervous system structures and functions
presumed germane to pain perception and transmission; from their results, the
presence, extent, and mechanisms of neuropathic pain are, at best, inferred. This
situation is similar to testing for diabetes mellitus using peripheral nerve,'
ophthalmologic, and renal studies without the availability of plasma glucose
2. There is a spectrum of clinical and pathophysiologic manifestations of neural
injury within each disorder, and chronic pain exists in only a small percentage of
affected patients. For example, neuropathic pain develops in approximately 16%
of patients with diabetes mellitus and a third of patients with diabetic
15neuropathy ; Postherpetic neuralgia, defined as chronic pain present 4 or more
months after resolution of the acute herpes zoster (shingles) rash, occurs in 13% to
1620% of shingles patients ; and after direct nerve injury during phlebotomy,
17persistent pain is rare, perhaps present after 1:1,500,000 procedures.
3. The presence of pain is presumed to reflect damage to the small myelinated
8(Aδ-) and unmyelinated (C-) nociceptive fibers within peripheral nerves. Because
these fiber types also mediate certain clinical functions that are measurable (e.g.,
perception of noxious and temperature stimuli and autonomic activity), many tests
have focused on demonstrating defects in these modalities to verify Aδ- or C-fiber
damage and invoke a basis for the pain.
Clinical Neurophysiology
Neurophysiologic testing, principally nerve conduction studies and
electromyography (EMG), are frequently employed in suspected disorders of the
peripheral nervous system. The usual techniques, with surface electrodes for nerve
stimulation and evoked potential recording, measure activity of the largest and
fastest conducting sensory and motor myelinated nerve bers (Aαβ-). The most
signi cant measured parameters are maximum nerve conduction velocity (NCV),
for the segment of nerve between the stimulating and the recording electrodes, and
amplitude and con guration of the resulting signals—the compound motor action
potential (CMAP) evoked from motor bers and the sensory nerve action potential
(SNAP) evoked from sensory bers. For central nervous system or proximal
peripheral nerve disorders, somatosensory and magnetic evoked potential studies
can be helpful. EMG is the needle examination of muscles and evaluates muscle
and motor nerve fiber activities.
Unfortunately, Aδ- and C- ber activities cannot be tested with these techniques.
Slowing in maximum NCVs and/or loss of CMAP or SNAP amplitudes occur as a
consequence of large ber dysfunction. Abnormal EMG features such as acute and
chronic denervation indicate involvement of large motor nerve bers from the
anterior horn cell distally. If present in a patient with neuropathic pain, these
abnormalities can corroborate the clinical impression of peripheral nerve damage
either individually or in general as in a polyneuropathy (e.g., diabetic or alcoholic
neuropathy). However, painful polyneuropathies or focal nerve lesions with'
exclusive or predominant small fiber involvement can have normal NCVs and EMG.
Nerve conduction studies may be of value in the serial investigation of patients who
present with painful small ber neuropathies, because there is indirect
electrodiagnostic evidence of progression to large ber involvement 5 to 10 years
after the onset of pain. However, some patients had preserved large ber functions
18over a 10-year period.
Quantitative Sensory Testing
Quantitative sensory testing (QST), used with increasing frequency especially in
clinical therapeutic trials, measures sensory thresholds for pain, touch, vibration,
and hot and cold temperature sensations. Commercially available devices range
from hand-held tools to sophisticated computerized equipment with complicated
testing algorithms, standardization of stimulation and recording procedures, and
comparisons with age- and gender-matched control values. With this technology,
speci c ber functions can be assessed: Aδ - bers with cold, cold-pain, and
mechanical pain detection thresholds; C- bers with heat and heat-pain detection
thresholds; and large ber (Aαβ-) functions with vibration detection thresholds and
11,19mechanical detection thresholds to von Frey hairs. Elevated sensory thresholds
correlate with sensory loss; lowered thresholds occur in allodynia and
19hyperalgesia. Certain QST ndings may relate to speci c pathophysiologic
mechanisms associated with neuropathic pain: heat hyperalgesia to peripheral
sensitization and static mechanical hyperalgesia or dynamic mechanical allodynia
11to central sensitization. In generalized polyneuropathies, when all quantitative
sensory thresholds are elevated, it is inferred that all ber types are a ected,
whereas if a dissociation exists wherein vibration thresholds are normal but the
other thresholds are elevated, a small ber neuropathy is suspected. In
asymptomatic patients, abnormal QST thresholds suggest subclinical nerve
The quantitation of an individual patient’s sensory perceptions, when compared
with normative values, gives a clearer distinction between normal and abnormal
responses and allows for analyses across patient and disease groups and for
baseline standards in longitudinal studies. Further, certain patterns of QST data
may have pathophysiologic signi cance. In two patients with postherpetic
neuralgia and similar levels of chronic pain, the QST results suggested peripheral
and central sensitization (heat hyperalgesia, mechanical hyperalgesia to pinprick
and blunt stimuli, allodynia to light touch) in one, and hyperactive dea erentation
of spinal cord neurons (thermal and mechanical hypoesthesia without hyperalgesia
11or allodynia) in the other.
The shortcomings of QST are: (1) It has never been used to di erentiate between
neuropathic and nonneuropathic pains, and QST abnormalities occur in'


3nonneuropathic pain conditions. (2) Abnormal ndings are not speci c for
peripheral nerve dysfunction; central nervous system disorders will also a ect
sensory thresholds. (3) Most signi cant, QST is a subjective psychophysical test
entirely dependent upon patient motivation, alertness, and concentration. Patients
can willingly perform poorly, and even when not doing so, there are large
intraand interindividual variations.
Autonomic Function Testing
The evaluation of autonomic functions in patients with suspected neuropathic pain
can be clinically useful because of anatomic similarities between pain and
autonomic bers outside the central nervous system and because disorders
associated with neuropathic pain frequently have signs and symptoms of
autonomic dysfunction (e.g., dry eyes or mouth, skin temperature and color
changes, sweating abnormalities, orthostatic hypotension, heart rate responses to
deep breathing, edema). The majority of autonomic tests study skin temperature
and sudomotor, baroreceptor, vasomotor, and cardiovagal functions; they have
20,21been extensively reviewed. A semiquantitative composite autonomic
symptoms score (CASS), composed of the results of sudomotor, cardiovagal, and
22adrenergic testing, has been devised. Pupillary, gastrointestinal, and sexual
function tests are occasionally helpful.
The value of autonomic testing in a generalized neuropathic pain disorder, small
ber neuropathy with burning feet, has been demonstrated in several studies of
patients with normal or only mildly abnormal electrophysiologic (NCVs/EMG)
23,24findings. Autonomic abnormalities were seen in greater than 90% of patients,
the most useful tests being the quantitative sudomotor axon re ex test (QSART),
thermoregulatory sweat test, heart rate responses to deep breathing, Valsalva ratio,
23,24and surface skin temperature. However, in a recent study of patients with
diabetic polyneuropathy, discordance was noted between e erent C- ber responses
in sudomotor tests (QSART and sweat imprint) and primary a erent (nociceptor)
C- ber axon-re ex are responses. These ndings indicate that these two C- ber
subclasses can be di erentially damaged or may have di erent patterns of
25regeneration and reinnervation. Abnormal autonomic functions can also occur in
painless peripheral neuropathies.
The relationship between autonomic dysfunction and pain is more complicated
in CRPS in which focal sudomotor and vasomotor abnormalities occurring at some
2, pp 39–43point in time are essential for the diagnosis, and sympathetic blockade
has been a mainstay of diagnosis and therapy for decades. As would be expected,
the vast majority of CRPS patients have autonomic abnormalities, particularly
26involving sweating and skin temperature. However, there are patients with'

identical focal pain, but no clinical evidence of autonomic dysfunction. These
patients do not meet the current de nition of CRPS and their condition has been
27termed “post-traumatic neuralgia.” Their autonomic functions have not been
well studied.
Skin Biopsy
Since the mid 1990s, the histologic analysis of unmyelinated cutaneous axons has
grown in importance in the diagnosis of peripheral nerve disorders, both
generalized and focal, including those associated with neuropathic pain. When a
skin punch biopsy is exposed to certain antibodies—most frequently, protein gene
product (PGP) 9.5—epidermal bers are labeled and can be visualized at
light28,29microscopic magni cations. Intraepidermal nerve ber (IENF) density and
morphology (e.g., tortuosity, complex rami cations, clustering, and axon swellings)
28,29 30can be quanti ed and compared with control values. A reduced IENF
31density is seen in idiopathic small ber neuropathies, diabetic neuropathy, and
32impaired glucose tolerance neuropathy, each of which is associated with
neuropathic pain. In one study, skin biopsy ndings were found to be a more
sensitive measure than QSART or QST in diagnosing neuropathy in patients with
33burning feet and normal NCVs. Conversely, disorders with severe loss of pain
sensation such as congenital insensitivity to pain with anhidrosis (hereditary
sensory and autonomic neuropathy IV [HSAN IV]) and familial dysautonomia with
sensory loss (Riley-Day syndrome [HSAN III]) also have severe loss of
intraepidermal bers, as does a predominantly large ber neuropathy, Friedreich’s
28,29ataxia, in which pain is unusual. Thus, the loss of IENFs is not speci c for the
presence of neuropathic pain.
A recent study suggests that the presence of large axonal swellings (>5 times the
nerve ber diameter) on an initial skin biopsy may predict progression of small
ber neuropathies, because this nding was associated with decreases in IENF
densities on subsequent biopsies. Also, those patients with these large axon
swellings were more likely to present with paresthesias (tingling or pins and
34needles) than with burning or “lightning” pains.
Additional tests of potential diagnostic value in patients with neuropathic pain,
particularly in focal pain syndromes such as CRPS, are bone scintigraphy, bone
densitometry, and nerve or sympathetic ganglion blockade. Serum
immunoelectrophoresis can be helpful in painful polyneuropathies associated with
monoclonal gammopathies and acquired amyloid polyneuropathy. Speci c serum
antibody tests are valuable in painful neuropathies associated with neoplasia,
35 3celiac disease, and human immunode ciency virus. Cruccu and associates also
noted that nociceptive re ex testing, laser-evoked potentials, and functional'
neuroimaging may be helpful in assessing function in nociceptive pathways but are
not widely used at this time. The latter two technologies may have great value in
the future.
Determining the causes of neuropathic pain is more than an epistemologic exercise.
At its essence, it is a quest to identify mechanisms of dysfunction through which
treatment strategies can be created to reduce, ameliorate, or eliminate
symptomatology. To date, predictors of which patients will develop neuropathic
pain or who will respond to speci c therapies are lacking, and present therapies
36have been developed mainly through trial and error. Our current inability to
make therapeutically meaningful decisions based on ancillary test data and de ned
mechanisms is illustrated by the following:
1. In assessing the response of patients with painful distal sensory neuropathies to
the 5% lidocaine patch, no relationship could be established between treatment
response and distal leg skin biopsy, QST, or sensory nerve conduction study
36results. From a mechanistic perspective, the hypothesis that the lidocaine patch
would be most effective in patients with relatively intact epidermal innervation,
whose neuropathic pain is presumed due to “irritable nociceptors,” and least
effective in patients with few surviving epidermal nociceptors, presumably with
36“deafferentation pain,” was unproved.
372. In Fabry’s disease, in which small fibers are exclusively affected, enzyme
replacement therapy failed to influence IENF density, had mixed effects on cold
38,39and warm QST thresholds, and had beneficial effects on sudomotor findings.
This occurred in the presence of clinical improvement as manifested in modest
39reductions in pain scores and in pain interference in daily life.
3. In a study of IENF density in diabetic patients with and without bilateral
symmetrical chronic neuropathic foot pain, “small fiber dropout does not always
parallel large fiber function and in fact differs between people with or without
pain depending upon the degree of sensory loss …. In individuals with little
objective sign of neuropathy, abnormalities of small nerve fibers are more likely to
play a central role in the genesis of pain. In those with severe objective signs of
neuropathy, a role of small fiber dysfunction in causing pain is still possible but
less certain, as there is a great deal of overlap in IENF [density] in those with or
40without pain.” The authors conclude that IENF loss “cannot explain pain in all
cases, suggesting that different mechanisms underpin the genesis of pain at various
40stages of neuropathy.”'
4. These same authors also report in diabetic patients that whereas QST is useful in
detecting the presence of neuropathy, and those with neuropathic pain had greater
sensory loss than those without pain, the abnormalities detected by QST do not
predict the presence of pain in diabetic neuropathy. They specifically state that
whereas the cold detection threshold is a sensitive indicator of neuropathy, it is not
a sensitive indicator for the presence of pain, and heat perception was even less
Along with the disparity in C- ber subtype involvement in diabetic small ber
25neuropathy, these results indicate that the speci city of ancillary testing and our
attempts to target mechanism-specific therapies in neuropathic pain are inadequate
at present and reinforce the aforementioned caveats about inferential conclusions
from indirect data. The diagnosis of neuropathic pain mechanisms is in its nascent
stages and ancillary testing remains “subordinate,” “subsidiary,” “auxiliary” (as
de ned in Webster’s Third New International Dictionary) to history and clinical
42-44Because of these diR culties and the lack of a diagnostic “gold standard,”
there has been renewed interest in patient symptoms and signs with the intent of
establishing clinical parameters indicative of neuropathic pain. Several
4,12,42-48questionnaires and scales have been developed, each using descriptors of
the types discussed in the “History” section, earlier, and based on several premises:
1. Determination of which chronic pain patients have neuropathic pain is
predicated upon observer interpretation of evidence of nervous system injury, for
example, “The clinical diagnosis was classified by the … clinician as nociceptive or
neuropathic pain based on clinical features, known pathology and radiological or
12electrophysiological evidence” ; “suspicion of neuropathic pain (by the referring
43physician)” ; “pain … which could be clearly attributed to a peripheral or
central nervous system injury … based on medical history, physical examination
46,47and electromyography, laboratory tests and/or imaging when indicated.”
2. There is a relationship between nervous system damage or dysfunction and a
special (neuropathic) pain with unique features. In these conditions, the clinical
features are not attributable to other etiologies.
3. The questionnaires and scales have the potential to isolate certain symptoms
and signs, which when present indicate that the pain is neuropathic. In their
absence, the pain is nonneuropathic in origin. One immediate concern with this
approach is the potential for circular reasoning—the criteria for classifying
patients into neuropathic or nonneuropathic pain groups include some of the
43outcome variables, thereby making the results self-fulfilling and logically
The results obviously vary from study to study, but one clear nding is that no
single or group of pain descriptors was dispositive for neuropathic pain. At its best,
12,44,48in the Bennett and colleagues’ studies, this approach attained 75% to 82%
success in correctly classifying pain type (sensitivity and speci city), with other
42,43,45-47studies reporting less than 73% accuracy. Even in the best-results
12,44,48studies, individual descriptors thought speci c for neuropathic pain (e.g.,
hot-burning, stabbing-shooting sensations) occurred in only 60% to 85% of de nite
neuropathic pain patients, and some of these same descriptors were seen in up to
one third of nonneuropathic pain patients. As a consequence, various authors of
these neuropathic pain questionnaires and scales have opined: “the overall picture
is that there are surprisingly few clusters of symptoms and signs in chronic pain
patients with either de nite or possible neuropathic pain, which are di erent from
43those that are unlikely to have neuropathic pain.” Also, “despite the ability of
the S-LANSS to classify patients, around 20% to 25%… were incorrectly classi ed;
some patients with nociceptive pain appear to have a number of features of
neuropathic pain and some patients with neuropathic pain appear to have few… .
it seems from the literature that at least 20% of patients with neuropathic pain are
44not identified by any existing tool that relies on assessment of clinical features.”
49Recognizing this enigma, Attal and Bouhassira and Bennett and his
48colleagues hypothesized (and provided data in support) that chronic pain can be
more or less neuropathic on a spectrum between “likely,” “possible,” and
“unlikely,” based on patient responses on neuropathic pain symptom scales, when
compared with specialist pain physician certainty of neuropathic pain on a
100mm visual analog scale. The symptoms most associated with neuropathic pain were
dysesthesias, evoked pain, paroxysmal pain, thermal pain, autonomic complaints,
and descriptions of the pain as being “sharp,” “hot,” “cold,” with high sensitivity.
Higher scores for these symptoms correlated with greater clinician certainty of
neuropathic pain mechanisms. There is, again, the logical conundrum of circular
reasoning at play here. There is also the surrender of the concept that neuropathic
pain is a unique phenomenon separate and distinct from other types of pain. It
remains to be seen whether considering each individual patient’s chronic pain as
being somewhere on a continuum between “purely nociceptive” and “purely
neuropathic” has diagnostic and therapeutic relevance.
Taken together, the clinical ndings and ancillary test results in patients suspected
10of having neuropathic pain have suggested to Hansson that: “Currently we lack
operational criteria for translating clinical symptoms and signs into identi ed
distinct pathophysiological mechanisms. Due to this shortcoming,… we are not in a'
position to extrapolate and make a safe bridging between clinical phenomenology
and pathophysiological mechanisms in animals. Therefore, a detailed
mechanismbased classi cation is currently not feasible.” I agree. We have moved from the
point at which we separated neuropathic pain from other types of pain by
recognizing similarities in the pain of patients with varied neurologic conditions, to
46,47realizing that neuropathic pain is, itself, highly heterogeneous and
multifactorial. Now, it may be bene cial to abandon the concept of neuropathic
pain as a single entity. The situation resembles that of Hans Christian Andersen’s
metaphorical child who, when watching the emperor’s processional, revealed what
all could see but none would admit.
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34. Gibbons CH, Griffin JW, Polydefkis M, et al. The utility of skin biopsy for
prediction of suspected small fiber neuropathy. Neurology. 2006;66:256-258.
35. Mendell JR, Sahenk Z. Painful sensory neuropathy. N Engl J Med.
36. Herrmann DN, Pannoni V, Barbano RL, et al. Skin biopsy and quantitative sensory
testing do not predict response to lidocaine patch in painful neuropathies. Muscle
Nerve. 2006;33:42-48.
37. Scott LJC, Griffin JW, Luciano C, et al. Quantitative analysis of epidermal
innervation in Fabry disease. Neurology. 1999;52:1249-1254.
38. Schiffmann R, Hauer P, Freeman B, et al. Enzyme replacement therapy and
intraepidermal innervation density in Fabry disease. Muscle Nerve. 2006;34:53-56.
39. Schiffmann R, Floeter MK, Dambrosia JM, et al. Enzyme replacement therapy
improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve.
40. Sorensen L, Molyneaux L, Yue DK. The relationship among pain, sensory loss, and
small nerve fibers in diabetes. Diabetes Care. 2006;29:883-887.
41. Sorensen L, Molyneaux L, Yue DK. The level of small nerve fiber dysfunction does
not predict pain in diabetic neuropathy; a study using quantitative sensory
testing. Clin J Pain. 2006;22:261-265.
42. Krause SJ, Backonja M-M. Development of a neuropathic pain questionnaire. Clin
J Pain. 2003;19:306-314.
43. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients
with suspected neuropathic pain. Pain. 2004;110:461-469.
44. Bennett MI, Smith BH, Torrance N, Potter J. The S-LANSS score for identifying
pain of predominantly neuropathic origin: validation for use in clinical and postal
research. J Pain. 2005;6:149-158.
45. Backonja M-M, Krause SJ. Neuropathic pain questionnaire—short form. Clin J Pain.
46. Bouhassira D, Attal N, Fermanian J, et al. Development and validation of theNeuropathic Pain Symptom Inventory. Pain. 2004;108:248-257.
47. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated
with nervous or somatic lesions and development of a new neuropathic pain
diagnostic questionnaire (DN4). Pain. 2005;114:29-36.
48. Bennett MI, Smith BH, Torrance N, Lee AJ. Can pain be more or less neuropathic?
Comparison of symptom assessment tools with ratings of certainty by clinicians.
Pain. 2006;122:289-294.
49. Attal N, Bouhassira D. Can pain be more or less neuropathic? Pain.
Chapter 4
Patricia Bruckenthal
Older adults often have multiple comorbidities that a ect the pain presentation. Whereas the goals of a
clinical assessment for pain in the older adult may be similar to those established for younger patients,
certain characteristics of aging make this assessment more challenging for clinicians. These
characteristics include reluctance of older individuals to report pain, the assumption that pain is a
normal part of aging, sensory and cognitive impairments, and fear of the consequences of
acknowledging pain, such as expensive testing or hospitalization. The pain experience can in uence
mood, physical functioning, and social interactions and indicates that pain assessment in older adults is
multidimensional and often a multidisciplinary responsibility.
The purpose of this chapter is to provide the clinician with the foundation to perform a successful
pain assessment for older adults who are able to communicate by self-report. This will provide a
comprehensive base on which to build a relevant plan of care. Pain assessment for those with cognitive
impairment is the focus of Section II, Chapter 5, Assessment of Pain in the Nonverbal and/or Cognitively
Impaired Older Adult.
Prevalence statistics for persistent pain in older adults range from 25% to 80%. Pain prevalence reports
1,2vary depending on whether the older adults reside in a nursing home, 45% to 80% or are community
3,4dwelling. The range reported for community-dwelling elders is 25% to 50%. Pain continues to be an
5,6under-assessed and under-treated condition in this population.
Lack of familiarity of common age-related changes and common painful conditions among the elderly
may contribute to the underrecognition of the problem. Many times, diagnostic imaging studies are
poorly correlated with the clinical expressions of pain. This may lead to confusion on the part of the
examining clinician and the potential for undervaluing the self-report of the patient and poor treatment
planning. A list of pain syndromes common in older adults is presented in Box 4–1.
Adapted from Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on
assessment of pain in older persons. Clin J Pain 2007;23(1 suppl):S1–S43; and Hanks-Bell, et al, 2004.
Musculoskeletal Conditions
• Osteoarthritis
• Degenerative disk disease
• Osteoporosis and fractures
• Gout
Neuropathic Conditions
• Diabetic neuropathy
• Postherpetic neuralgia
• Trigeminal neuralgia
• Central poststroke pain
• Radicular pain secondary to degenerative disease of the spine
Rheumatologic Conditions
• Rheumatoid arthritis
• Polymyalgia rheumatica
• Fibromyalgia
Musculoskeletal pain is one of the most common types of pain experienced by community-dwelling
7-9older adults. The underlying disorders responsible for chronic low back pain (CLBP) are varied and
require speci c physical examination techniques. For example, of 111 older adults with CLBP, 84%
reported sacroiliac joint pain, 19% reported pain consistent with bromyalgia, 96% myofacial pain,
10and 48% hip pain. Rheumatic diseases, characterized by in ammation, degeneration, or metabolic
disorders, are the most common diseases reported by older adults residing in long-term care (LTC)
11facilities. Specific examination techniques for musculoskeletal disorders are discussed later.
Functional, cognitive, emotional, and societal consequences have been associated with unrelieved
pain in older adults. Decreased activity due to pain can lead to myofacial deconditioning and gait
disturbances, which in turn, can result in injuries from falls. Appetite impairment has been reported in
community-dwelling adults with pain intensity scores higher than in those without appetite
12 13impairment. Pain in the elderly has been associated with increased sleep disturbances. These
consequences can lead to less than optimal participation in rehabilitation e orts and decreased quality
of life in general. Increased costs due to health care utilization have also been implicated as a result of
14unrelieved pain in the elderly. Consideration of the unique characteristics included in the history and
physical assessment for pain in older adults will assist clinicians in the development and implementation
of an individualized treatment plan that will optimize successful outcomes.
A comprehensive, multidimensional pain assessment in older adults will ultimately lead to a more
successful individualized plan of care. Regardless of whether the pain is acute, postoperative, or
chronic, the goal of the assessment is to identify the cause of pain, conduct a thorough history of
comorbid medical and psychosocial conditions, and perform an appropriate physical examination and
diagnostic work-up. Often, a multidisciplinary approach may be needed, and after the initial
assessment, the clinician may determine that referral to an appropriate specialist is necessary for
specialized services or skilled procedures. For example, a mental health professional may be able to
optimize a plan to treat depression or a substance abuse disorder or a physical therapist may be
consulted for evaluation of a conditioning program. A review of existing medical records is also
beneficial to the assessment process.
History of the Pain Complaint
Several elements are recognized as essential for a comprehensive assessment of pain at any age. One
such schema recommended for guiding a comprehensive pain assessment in older adults is outlined in
detail in the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)@

15-18project. Included in this review are necessary elements such as nuances speci c to older adults to
assist the clinician in the assessment process. Techniques for assessing these age-speci c elements are
described later.
Self-report of pain is still considered the most reliable source for the cognitively intact and
19communicative older adult’s pain complaint. Sensory de cits in vision, hearing, and cognition are
common in this population and need to be identi ed prior to beginning the interview. These may a ect
the patient’s ability to complete the assessment process, and adjustments to accommodate for de cits
need to be considered. This may become especially relevant when selecting appropriate pain assessment
instruments. It also may be bene cial to query other family members or caregivers for additional
perspectives on medical history, predominant mood and affect, and physical and social functioning.
Present Pain Complaint
Assessment of the pain characteristics includes a detailed description of the onset, duration, frequency,
intensity, location, and contributing factors. For a variety of reasons, older adults may not be
forthcoming regarding reports of pain. They also may use descriptions other than pain to describe what
they are experiencing. It is common for older adults to use terms such as “aching,” “soreness,”
20,21“hurting,” “discomfort,” or other descriptors.
The onset and timing are important considerations. Wheras degenerative musculoskeletal disorders
generally have an insidious onset, a change in character from a less severe to a more intense pain may
indicate a progression of disease or a new-onset fracture. Pain that is more intense in the morning is a
feature of cancerous bone pain. Tools to evaluate pain intensity speci c to the geriatric population have
been identi ed and are outlined later. Older persons are able to utilize a body pain map or diagram to
22,23indicate the location(s) of their pain. Sometimes, the pain, although not present during rest, will
manifest itself during activities and, therefore, this too should be explored with the patient. A useful
structured interview technique that will elicit information on the present pain complaint for older adults
who can communicate is suggested in Box 4–2. Associated symptoms, such as paresthesias, may
indicate radicular involvement of an extremity in pain. Fever or weight loss may herald more ominous
diagnoses including infection or malignancy.
Reprinted with permission from Weiner D, Herr K. Comprehensive interdisciplinary assessment and treatment
planning: an integrative overview. In Weiner D, Herr K, Rudy T (eds): Persistent Pain in Older Adults: An
Interdisciplinary Guide for Treatment. New York: Springer, 2002; pp 18–57.
1. How strong is your pain (right now, worst/average over past week)?
2. How many days over the past week have you been unable to do what you would like to do because
of your pain?
3. Over the past week, how often has pain interfered with your ability to take care of yourself, for
example with bathing, eating, dressing, and going to the toilet?
4. Over the past week, how often has pain interfered with your ability to take care of your
homerelated chores such as going grocery shopping, preparing meals, paying bills, and driving?
5. How often do you participate in pleasurable activities such as hobbies, socializing with friends, and
travel? Over the past week, how often has pain interfered with these activities?
6. How often do you do some sort of exercise? Over the past week, how often has pain interfered with
your ability to exercise?
7. Does pain interfere with your ability to think clearly?


8. Does pain interfere with your appetite? Have you lost weight?
9. Does pain interfere with your sleep? How often over the past week?
10. Has pain interfered with your energy, mood, personality, or relationship with other people?
11. Over the past week, how often have you taken pain medications?
12. How would you rate your health at the present time?
Past Medical History
This review should include a history of past medical, surgical, and psychiatric conditions, as well as
accidents/injuries. Dates of onset, current and past treatments, and treating practitioners should be
obtained. Eliciting this information is important for several reasons. The existence of certain comorbid
conditions will a ect treatment decisions for pain. For example, nonsteroidal anti-in ammatory agents
may be of limited use in those with a history of heart disease or hypertension. Patients with liver disease
will need to use acetaminophen cautiously. Preexisting renal disease will affect the use of medications as
well. Identification and documentation of preexisting conditions will facilitate treatment planning.
Knowledge of the pattern of certain preexisting conditions can also help with anticipatory planning.
Sensory distal polyneuropathy is the most common neurologic presentation in patients with diabetes
mellitus. Although most polyneuropathies are painless, 7.5% of patients report unpleasant sensations of
24pain. Clinicians should be alert to evolving sensory complaints in diabetic patients, especially those
with poor glycemic control. Musculoskeletal disorders that have changed in presentation may signal
progression of disease and may require more intense investigation. Finally, results of any previous
laboratory and diagnostic tests should be reviewed not only to guide future treatment decisions but also
to avoid unnecessary repeat testing.
Medication History
A careful medication history must be inclusive of all current and past medications, dosages, side e ects,
and response. This consists of prescribed, over-the-counter, and herbal supplements. Alcohol use should
be speci c to frequency and amount. Tobacco products and illicit drug use are important elements of
inquiry as well. It is important to obtain the name and phone number of the current pharmacy(ies)
Functional Assessment
Essential elements of a functional assessment are broad and include cognitive, physical, and
psychosocial dimensions. Data from these aspects of the assessment establish a baseline to enable the
clinician to determine speci c goals, the extent to which the patient can participate, and response to the
treatment plan.
Cognition is grossly assessed during the process of the health interview. Some areas of cognitive
decline, such as uid reasoning, processing speed, and short-term memory, are part of the normal aging
25,26process. Factors other than dementia that should be considered as causative in cognitive decline
25 27include poor nutritional status, medication e ect, depression, living environment, and pain. The
28Mini-Mental State Examination (MMSE) can be used to assess cognition, but it may not be able to
pick up subtle changes. A more complete discussion on pain assessment in the cognitively impaired
adult is addressed in detail in Section II, Chapter 5, Assessment of Pain in the Nonverbal and/or
Cognitively Impaired Older Adult.
Physical function incorporates the assessment of mobility, activities of daily living (ADLs), sleep
pattern, and appetite. The clinician should ascertain the current level of physical activity and mobility
the patient is capable of. This includes an assessment of the level at which basic ADLs are being

performed. It is helpful to identify activities previously preformed that the pain prohibits the patient
from doing currently. Ask if the patient engages in a regular exercise program. These assessment
parameters should establish the baseline of current physical function.
Questions regarding sleep patterns are asked to evaluate whether restorative sleep is being attained.
Poor sleep may be the result of the aging process, depression, or pain. Identifying the cause will assist in
developing an appropriate intervention for improving sleep. Appetite suppression has been associated
12with a higher pain intensity level in community-dwelling adults. Poor nutrition can contribute to
fatigue and diminished function and well-being. By reviewing all the pertinent aspects of function, the
clinician and patient can begin to establish realistic treatment goals in this domain.
Psychosocial Assessment
Mood, social support systems, recreational involvement, and nancial resources are important to the
psychosocial assessment. These factors all in uence the pain experience and how the patient in pain
functions in these domains as well as responds to various treatments.
13,29-31Depressive disorders are prevalent in people with chronic pain. Patients who are depressed
may exhibit decreased energy and engagement in treatment modalities or avoidance of pleasant
32diversional activities. The Geriatric Depression Scale (GDS) is one instrument that can be used to
determine whether further evaluation for depression is indicated. This instrument is of particular bene t
33,34in residential care elders, whereas the Center for Epidemiological Studies Depression Scale (CESD)
35is more suited for community-dwelling elders.
36,37Anxiety has also been closely associated with pain and often coexists with depression in this
population. Anxiety may play a part in fear-related behavior that might inhibit participation in physical
rehabilitation e orts. It may be useful for the clinician under these circumstances to evaluate this
38disorder in more detail. The Beck Anxiety Inventory is a brief screening tool that has been used in the
elderly for evaluating anxiety symptoms. A distinction can be made between a situational anxiety
response and the more enduring personality anxiety trait, and these can be evaluated using the
State39Trait Anxiety Inventory. While eliciting trait versus state anxiety traits, it may be noted that in pain
patients, the relationship between transient and enduring emotional responses to pain and outcomes to
treatment intervention need to be further explored. Emotional responses of depression and anxiety,
however, do have an impact on the overall pain experience and are essential to the overall assessment.
Assessment of the social support network and economic status for older people in pain is important on
several levels. Involvement with family and friends can provide pleasurable experiences and diversion
away from a constant focus on pain. Supportive social contacts can provide transportation to clinic and
treatment appointments. Osteoarthritis patients who participated in spouse-assisted pain-coping skills
training had a greater reduction on pain and disability outcomes that those who participated in
40conventional nonspousal participant training. In addition to the availability of social support, the
type of relationship should be assessed. Negative social reinforcement may present in the form of overly
solicitous family members who encourage sedentary behavior. Other negative e ects are likely if
longterm caregivers become resentful of their support role. Finally, economic resources have a great impact
on access to potential treatment options and must be identified.
Beliefs and Attitudes about Pain
The context in which older adults perceive pain is relevant to the overall assessment. Pain can signify
loss of independence or debilitating illness or be regarded as a general consequence of the aging process
and therefore be underreported. Better treatment satisfaction and outcomes are reported when there is
greater agreement between patient beliefs about the nature and treatment of pain and the treatment
Multiple constructs associated with beliefs and attitudes about pain have been studied and have an@

impact on the total pain experience and outcomes. Many of these are interrelated, such as coping,
selfefficacy, catastrophizing, and pain-related fears. Coping and self-efficacy are discussed later.
42-44Two simplistic models of coping have been described as active versus passive and adaptive
45,46versus maladaptive coping. Patients use a variety of coping skills for managing pain. For example,
task persistence, activity pacing, and use of coping self-statements were coping strategies most
47frequently used by a group of predominantly female older adults living in retirement facilities. Prayer
48is often utilized by older adult women as a coping mechanism for pain. Identifying coping skills
among the elderly is important so that the clinician can encourage the use of previously successful skills
or modify treatment interventions to incorporate teaching e ective coping skills. Patients with passive
49or maladaptive coping styles would likely bene t from psychological interventions that would focus
on more effective ways of coping.
50,51Self-efficacy refers to the belief that one can control or manage certain outcomes of one’s life.
Beliefs about the degree of control and self-eJ cacy in being able to manage pain have been well
52,53 54studied and are related to types of coping strategies used to manage pain. Participation in
cognitive-behavioral pain-coping skills interventions can increase self-eJ cacy beliefs and have been
40,55-57shown to decrease pain intensity, disability, and depression. Patients who are identi ed as
having poor beliefs regarding their ability to manage pain may bene t from coping skills training aimed
at increasing self-eJ cacy. Examples of instruments that measure one’s perceived ability to manage pain
are listed in Table 4–1.
Table 4–1 Selected Instruments for Pain Assessment in Older AdultsPain Assessment Measurement Instruments
An abundance of reliable and valid instruments are available to assist in the assessment of pain. The
choice of which to use will depend on factors including purpose of the tool, clinical setting, and time@


constraints. Some instruments measure a single pain construct whereas others are multidimensional.
Clinicians are encouraged to nd instruments that are useful to their clinical needs and encompass the
broad pain assessment domains covered in this chapter.
Table 4–1 represents a sample of pain assessment instruments that were extrapolated from reviews by
18 58 59Hadjistavropoulos and coworkers, Gibson and Weiner, and Herr and Garand. Many of these are
self-assessment/self-report instruments and can be administered prior to the history and examination
portion of the pain assessment and reviewed by the clinician with the patient. The choice of tools can be
18overwhelming. As a pragmatic yet comprehensive approach, Hadjistavropoulos and coworkers
60recommended the administration of the Brief Pain Inventory (BPI) and the Short-Form McGill Pain
61Questionnaire (SF-MPQ) as suitable for most cognitively intact older adults. These cover the
multidimensional nature of the pain assessment and can be completed in approximately 10 minutes.
Instruments that measure pain in cognitively impaired elders are covered in Section II, Chapter 5,
Assessment of Pain in the Nonverbal and/or Cognitively Impaired Older Adult.
Physical Assessment
The focus of the physical assessment will vary depending on whether the pain complaint is acute or
chronic. In general, in ammation, traumatic injury, and cancer-related conditions are associated with
acute pain, whereas neurologic and musculoskeletal etiologies cause more chronic pain conditions. This
section focuses on the latter assessment and suggestions for the former are included in the discussion of
assessment of speci c painful conditions. All patients should have a brief examination of general health
status, including vision and hearing, cardiovascular, respiratory, and gastrointestinal systems, prior to
the more focused examination.
When the painful region is examined, inspection is focused on signs of in ammation, trophic changes,
joint deformity, and vascular signs such as paleness, cyanosis, or mottled appearance.
Musculoskeletal Examination
Assessment of the musculoskeletal system focuses on inspection of any joint deformities and disuse signs
such as asymmetry of muscular bulk and tone. Note any spinal deformity including kyphosis, lordosis,
or scoliosis. Palpation includes the spinous processes and paraspinal muscles, sacroiliac joint, piriformis,
or the bromyalgia tender points for more generalized pain complaints. During range of motion of the
cervical spine, lumbar spine, and hip, the quality, quantity, and elicitation of pain should be noted.
Speci c examination maneuvers can o er clues to the etiology of the pain complaint. Straight leg
raising, Lasègue’s sign, is indicative of nerve root compression. Crossed straight leg raising, exacerbation
of leg pain when the contralateral leg is raised, may suggest lumbar disk herniation. Fabere maneuvers
(Patrick’s test) include exion, extension, abduction, and external rotation of the hip. Pain during these
movements is suggestive of degenerative joint disease of the hip, but it may also occur with sacroiliac
pathology. Pain radiating down the arm produced by lateral tilt or rotation of the head (Spurling’s sign)
in patients complaining of neck pain may indicate cervical nerve root compression. Lhermitte’s sign is
an electric shock–like sensation in the torso or extremities associated with cervical exion and may be
62suggestive of a cervical cord lesion.
Pain is a contributing factor of mobility impairment and falls in the elderly and warrants an assessment
of gait and balance. Gait changes associated with aging include decreased step length, walking speed,
ankle range of motion, and the ability to push-o with the toes. The ability to rise unassisted from a
63 64seated position to standing, timed and averaged for 5 repetitions, and the timed “up and go” test
are simple, quick measures of basic functional mobility.@


When conducting a focused neurologic examination, strength, sensation, and deep tendon re exes are
assessed. In general, a sensory dermatomal level usually correlates with the anatomic level of the lesion.
Hyperalgesia, hyperpathia, and hypoesthesia can be tested by pinprick. Allodynia is tested using a
cotton swab or paintbrush. Hypore exia may indicate nerve root compression whereas hyperre exia
may be indicative of myelopathy from spinal cord compression. Decreased vibratory sensation and
hyporeflexia are signs consistent with peripheral neuropathy.
The physical assessment is important to help con rm etiology and identify level of impairment, to
determine level of function, and to elicit emergent conditions in the older population. Ongoing physical
assessment continues to be imperative in order to evaluate the e ectiveness of treatment, exacerbation
of identi ed conditions, or the emergence of new problems that need attention. Therefore, a follow-up
physical examination guided by the medical history should take place at each subsequent visit.
Trigeminal Neuralgia
Trigeminal neuralgia is characterized by severe, unilateral facial pain described as lancinating, electric
shock–like jolts in one or more distributions of the trigeminal nerve. The maxillary and mandibular
divisions are most commonly a ected. The causes vary by age. In the elderly, compression of the
trigeminal root by an artery or vein or both is the cause about 80% of the time. Intracranial tumors and
demyelinating disease have also been implicated. The characteristic jabs of pain last from 2 to 120
seconds and are often precipitated by activities such as brushing, chewing, or talking. The paroxysms of
pain are separated by pain-free intervals. Because there are no cranial nerve de cits, the diagnosis of
tumor may be delayed. Careful clinical evaluation and magnetic resonance imaging (MRI) are
65recommended for all patients presenting with trigeminal neuralgia.
Postherpetic Neuralgia
Postherpetic neuralgia (PHN) is a frequent complication after an outbreak of herpes zoster in the
elderly. Sensory ndings include allodynia or hyperalgesia in the associated dermatomal region, the
thoracic being more common than the facial. Patients with allodynia complain of the wind or a piece of
clothing causing pain. Hyperalgesic patients describe provocation of pain by a relatively mild stimulus,
such as bumping up against a piece of furniture. Tingling, severe itching, burning, or steady throbbing
pain have also been described. Pain associated with PHN can interfere with ADLs and quality of life,
65and therefore, identification and intervention are crucial.
Poststroke Pain
Poststroke pain, an underrecognized consequence after stroke, occurs in 33% to 40% of patients who
have had a stroke. The pain may present as shoulder pain in the paretic limb or present as central
poststroke pain (CPSP). CPSP is characterized as pain that is severe and persistent with accompanying
66,67sensory abnormalities.
Metastatic Bone Pain
Bone pain that is worse at night, when lying down, or not associated with acute injury should raise
suspicion of metastatic disease. Also, pains that gradually but rapidly increase in intensity or with
weight bearing or activity are suspicious. Frequent sites of metastatic pain include the hip, vertebrae,
femur, ribs, and skull. Examination includes palpation of the affected site.
Temporal Arteritis
Greater than 95% of the cases of temporal arteritis occur in patients over 50 years old. Presentation@


includes complaints of new-onset headache, malaise, scalp tenderness, and jaw claudication. Physical
examination reveals an indurated temporal artery that is tender with a diminished or absent pulse.
Because irreversible blindness is a consequence if untreated, timely assessment and treatment are
68essential. Generally, patients are started on glucocorticoids while awaiting temporal artery biopsy.
Much of the current literature on pain assessment and information provided in this chapter seem most
suited for elders with chronic rather than acute pain. Psychosocial factors are more closely associated
with chronic pain states and have been studied more intensely. The nature of the pain being evaluated
and the setting of the evaluation will dictate which assessment techniques are warranted. Whereas
scales that measure pain intensity can be administered rapidly and are suitable for any setting, others
require more time and are more likely to be helpful in the primary care oJ ce/clinic or LTC facility.
Some distinctions regarding the setting and type of pain are provided later.
Acute Pain
Older adults who present with acute pain require a rapid assessment including a self-report of pain
intensity and other descriptors of the present pain complaint. Past pain history and medication history
are also essential. Completion of a more comprehensive assessment can be delayed until the etiology
and treatment of the pain has been initiated. Ongoing monitoring of the pain intensity, duration, and
e ects of treatment should take place every 2 to 4 hours initially. Once every 8 hours is appropriate
69once the pain is well controlled. Older adults may use terms other than pain, so questions that relate
20to discomfort and hurting may need to be asked. The patient should be observed during an activity
such as ambulation, transfers, or repositioning, because behavior and pain levels may not be equal
20during different activities.
Autonomic responses such as increased heart rate and blood pressure and altered respiratory rate are
generally associated with acute pain. The clinician should be cautioned that the absence of these signs
70does not indicate that pain is not present. In fact, no statistically signi cant di erences were seen
between self-reported pain scores and heart rate, blood pressure, or respiratory rate in adult patients
71presenting to an emergency department for a variety of acute painful conditions. Clinicians should
not rely on vital signs as the sole indicator for the presence or degree of acute pain. Patient self-report of
pain remains the “gold standard.”
LTC Facility
Pain assessment in nursing homes continues to be a challenge. Common themes regarding pain
assessment in LTC facilities persist. Two studies illustrate the significance of this problem.
72Clark and colleagues conducted a qualitative study using focus groups in 12 nursing homes in
Colorado. They identi ed that within nursing homes (1) there is an uncertainty in pain assessment, (2)
that relationship-centered cues to residents’ pain are a solution to limitations of formal assessment, (3)
cues to pain are behavioral changes and observable physical changes, and (4) speci c residents’
characteristics, such as attitudes or being perceived as “diJ cult,” made pain assessment more
challenging. These ndings have implications for practice. Education of sta regarding the complex
nature of chronic pain and its psychosocial domains may help clarify the ambiguity expressed regarding
assessment. Acknowledging the importance of family members’ and certi ed nursing assistants’ reports
of behavioral and physical changes is essential to the process. The use of pain assessment tools
appropriate for diJ cult patients or patients with communication impairment is helpful. It has been
reported that the availability of various assessment tools to suit patient preferences will increase the
73frequency of diagnosing pain in nursing home residents.
74Similarly, Kaasalainen and coworkers found that pain assessment was problematic in nursing@

homes and that appropriate pain assessment strategies were closely linked to e ective pain
management. Common themes emerged of negative myths about pain and aging, inadequacy of current
tools used in practice, and the inability to discriminate between pain and problems such as dementia
and delirium. This lack of confidence in assessment was reflected in the ways that pain was treated.
These ndings suggest that engaging in a process committed to pain assessment at all levels in the
LTC facility will have positive implications for management of pain in this setting. Two useful resources
to facilitate implementing an institutional plan are described in the American Geriatric Society Panel on
19Persistent Pain in Older Adults and the American Medical Directors Association Chronic Pain
75Management in the Long Term Care Setting guidelines. These evidence-based interdisciplinary
guidelines form a basis for a comprehensive pain management program that includes recognition,
assessment, treatment, and monitoring recommendations.
An accurate assessment of pain provides the foundation for a successful treatment plan in the older
adult. This assessment is often complex and multidimensional and varies depending on the practice
setting in which the patient is encountered. Self-report remains the most reliable measure of the painful
complaint. Self-report should be supplemented with existing medical records, information from family
members and caregivers when possible, and the utilization of additional instruments available to
measures pain-related constructs.
The sheer range and choice of pain-related measurement instruments can be daunting for the
clinician. In many cases, particularly when evaluating an older adult with a chronic pain complaint, the
process can be time consuming. Many assessment instruments can be given to the patient prior to the
evaluation process and reviewed with the patient during the examination. One suggestion toward a
rational approach to assessment is described earlier and includes self-report, the BPI, and the SF-MPQ.
Other assessment instruments can be added depending on particular needs of speci c populations
common to a practice setting. The objective is to make sure the assessment is comprehensive and
includes an evaluation of the multidimensional facets of pain in older adults.
The initial evaluation is only the beginning of the assessment process. Ongoing clinical monitoring of
treatment outcomes or the development of new clinical ndings includes reassessment at appropriate
intervals, documentation, and communication of ndings to all members of the health team involved in
care. By implementing a systematic process in pain assessment, clinicians can develop goals and
treatment protocols that will ultimately optimize pain management in older adults.
1. Proctor WR, Hirdes JP. Pain and cognitive status among nursing home residents in Canada. Pain Res
Manage. 2001;6:119-125.
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Karen Bjoro, Keela Herr
Pain is a highly subjective and personal experience. Self-report is widely accepted as the most reliable
source of information on an individual’s pain experience and is considered to be the “gold standard” in
1,2most populations. Yet, older adults with severe cognitive impairment or who are unconscious and/or
intubated during an episode of severe critical illness are unable to communicate their pain experience.
The inability to use verbal language represents a major barrier to pain assessment and treatment. For
these individuals, alternative approaches to pain assessment, involving observation of pain behaviors
and proxy pain reports, are necessary.
The ability to use language is a comprehensive and complex behavior acquired in early childhood.
The primary faculties of language include speaking, signing, and language comprehension, whereas
3reading and writing are secondary abilities. With language impairment (e.g., aphasia, dysphasia), the
ability to communicate orally, through signs, or in writing or the ability to understand such
communications may be severely compromised. Language impairment (e.g., aphasia, dysphasia) is
associated with many medical illnesses and clinical states (Box 5–1). The loss of ability to communicate
is a core feature of many types of cognitive impairment (e.g., dementia, delirium) and occurs frequently
with severe critical illness as well as at the end of life, with the naturally occurring deterioration in
cognition resulting from ensuing death and/or sedation.
• Dementias
• Delirium
• Cerebrovascular accident
• State of unconsciousness/advanced life support/intubation
• Severe depression
• Psychosis
• Mental disability
• Coma, persistent vegetative state
• Encephalopathy
• Terminal illness
The purpose of this chapter is to review the current basis for pain assessment in three nonverbal
populations: those with advanced dementia, those with delirium, and those experiencing an episode of
critical illness who are unable to communicate owing to an unconscious state or the presence of anendotracheal tube. General principles of pain assessment and speci8c recommendations for pain
assessment of nonverbal older adults are discussed. Finally, a selection of behavioral pain assessment
tools for use with these nonverbal older adults is critiqued.
Dementia is one of the most frequent causes of cognitive impairment in older adults, with a forecast
4worldwide increase in incidence from 25 million in 2000 to 114 million by 2050. Dementia involves
the development of multiple cognitive de8cits manifested by impaired memory and involving cognitive
disturbances and the loss of language, the ability to recognize or identify objects, and executive
5function. As dementia progresses to advanced stages, individuals become increasingly dependent in all
activities of daily living, often requiring skilled nursing care.
The burden of dementia in the older adult population is compounded by a considerable pain
6burden. In institutionalized older adults with dementia, pain or potentially painful conditions are
7,8common, with prevalence estimates ranging between 49% and 83%. One large-scale nursing home
study documented that half of the residents reported having pain in the past week and a fourth
9experienced pain daily. Moreover, a similar prevalence of pain was documented in subgroups of
cognitively intact and impaired residents. The most common pain-associated conditions in the
cognitively impaired residents were arthritis, previous hip fracture, osteoporosis, pressure ulcers,
9depression, and a history of a recent fall, unsteady gait, and verbally abusive behavior.
The severity of cognitive impairment and the progression of language de8cit vary by type and stage
of disease, environmental factors, and individual characteristics. In Alzheimer’s disease (AD), which
accounts for over half of dementia cases, memory de8cit is the presenting symptom, with language
10impairments developing gradually over the course of the illness. Typically, AD patients are Duent
until the middle to late stages of the disease, whereas global language disturbance and mutism are
generally present in the end stage of AD. With vascular dementia, the second most prevalent type, the
11trajectory of language impairment resembles that observed in AD. By comparison, individuals with
frontotemporal dementia (behavioral type) and primary progressive aphasia show earlier onset of
10language impairment and more rapid decline. The subtype of dementia also appears to aEect pain
response. In frontotemporal dementia, a decrease in aEective pain response has been documented that
could be explained by atrophy of the prefrontal cortex. In contrast, with vascular dementia, an increase
in aEective response is reported that may be related to white matter lesions and deaEerentiation in
12these patients.
Neuropathologic processes in dementia seriously aEect the ability of those with advanced stages of
disease to communicate pain. However, only a few studies have investigated the relationship between
dementia and the neuropathology of pain, and these are limited to experimental pain studies in
individuals with AD. Whereas sensory discriminatory aspects of pain are processed in the lateral pain
system (e.g., lateral thalamus), motivational aEective aspects are processed in the medial pain system
13,14(e.g., anterior cingulate gyrus, hippocampus). Noxious stimuli transmitted via the lateral pain
system are interpreted in the somatosensory cortex, involving areas of the brain that are relatively
unaEected by AD neuropathology. This explains the 8nding that sensory aspects of pain remain intact
in individuals with AD. Nevertheless, the lateral pain system does show some functional decline, as
evidenced by an elevated pain threshold and reports of less intense pain in those with AD. By contrast,
12,15the medial pain system is severely aEected by pathologic processes in AD. The aEective pain
response (e.g., pain tolerance) was signi8cantly increased in individuals with AD compared with those
12without dementia. Thus, empirical studies indicate that older adults with dementia are not less
sensitive to pain but they may fail to interpret sensations as painful.
Despite these 8ndings, evidence suggests that older adults with advanced dementia underreport paincompared with those who are cognitively intact. Research studies have documented a decrease in the
number of pain complaints with increasing severity of cognitive impairment in older adults with
16,17dementia. Inability to communicate is a major barrier to adequate pain assessment and treatment
in older adults with advanced dementia. Cognitively impaired older adults hospitalized with a hip
18,19fracture received signi8cantly less opioid analgesia than those with less or no impairment. In the
nursing home setting, pain is documented less frequently in residents unable to communicate their pain,
9,20,21even though they have a similar number of painful diagnoses. Moreover, less analgesia is
prescribed and administered for cognitively impaired nursing home residents, even when the impaired
22,23residents have numbers of painful diagnoses similar to those in cognitively intact residents. Thus,
the inability to communicate in older adults with dementia is a major barrier to both assessment and
treatment. Language impairment is also common in delirium.
Delirium is a form of transient cognitive impairment often accompanied by loss of the ability to
communicate eEectively. The incidence of delirium in older adults ranges from 16% to 62% with hip
24 25 26fracture, 62% in the intensive care unit (ICU), 25% to 45% in older cancer patients, and
27approximately 22% in nursing home residents.
Delirium is characterized by recent onset of Ductuating awareness and an inability to focus attention,
a change in cognition (e.g., memory de8cit, disorientation) or perceptual disturbance, and the presence
5of an underlying organic illness. There are three clinical subtypes of delirium: hyperactive, hypoactive,
28and mixed. Language disturbance in delirium is characteristically manifested by an impaired ability
to articulate, name objects, write, or even speak. Speech may be rambling and irrelevant or pressured
5and incoherent, with unpredictable shifting from subject to subject. Thus, although older adults with
delirium may be able to speak, the content may be incomprehensible.
Although the pathophysiology of delirium remains unclear, there is general agreement that delirium
29,30 29etiology is multifactorial. Inouye and Charpentier proposed that delirium may develop in a
vulnerable individual owing to the interaction of predisposing and precipitating risk factors.
Predisposing factors (e.g., high age, dementia, multiple chronic diseases) increase the vulnerability of an
individual to noxious factors that interact with the underlying predisposing factors to precipitate the
onset of delirium. Whereas many potential precipitating factors have been identi8ed (e.g., dehydration,
electrolyte disturbance, polypharmacy, infection, hypoxia), delirium onset has also been linked to
31 32antecedent pain in hip fracture patients, medical patients, and older adults undergoing elective
33,34 31,35surgery. However, many of the analgesics (e.g., meperidine ) and other adjuvant medications
35used to treat pain (e.g., benzodiazepine ) can also trigger the onset of delirium. The relationship
between pain, pain treatment, and delirium is complex and unclear.
Pain assessment in older adults with delirium is extremely challenging. No diagnostic tests exist to
determine the presence of either pain or delirium. Identi8cation of pain in nonverbal older adults and of
delirium both rely on observation of behavioral presentation. Moreover, there is considerable overlap
36between delirium behaviors and nonverbal pain behaviors. Liptzin and LevkoE used behavioral items
37on the Delirium Symptom Interview to observe hypoactive and hyperactive behaviors of patients with
delirium (Table 5–1). Interestingly, many behavioral symptoms of delirium also occur on a
comprehensive list of nonverbal pain behaviors (Table 5–2) (e.g., wandering, verbally abusive behavior,
resistiveness to care).
Table 5–1 Delirium Subtype and Associated Potential Behavioral Symptoms
Delirium Subtype Behavioral SymptomsHyperactive
Fast or loud speech
Easy startling
Fast motor responses
Persistent thoughts
Decreased alertness
Sparse or slow speech
Slowed movements
Based on Liptzin B, Levkoff SE. An empirical study of delirium subtypes. Br J Psychiatry 1992;161:843–845.
Table 5–2 Common Pain Behaviors in Cognitively Impaired Older Persons
Behavior ExamplesFacial expressions Slight frown, sad, frightened face
Grimacing, wrinkled forehead, closed or tightened eyes
Any distorted expression
Rapid blinking
Verbalizations, vocalizations
Sighing, moaning, groaning
Grunting, chanting, calling out
Noisy breathing
Asking for help
Verbal abusiveness
Body movements
Rigid, tense body posture; guarding
Increased pacing, rocking
Restricted movement
Gait or mobility changes
Changes in interpersonal interactions
Aggressive, combative, resists care
Decreased social interactions
Socially inappropriate, disruptive
Changes in activity patterns or routines
Refusing food, appetite change
Increase in rest periods
Sleep, rest pattern changes
Sudden cessation of common routines
Increased wandering
Mental status changes
Crying or tears
Increased confusion
Irritability or distress
From American Geriatrics Society (AGS) Panel on Persistent Pain in Older Persons. The management of persistent
pain in older persons. J Am Geriatr Soc 2002;50:S211. Used with permission.
Few studies have investigated pain assessment in older adults with ongoing delirium. One study
showed that physicians and nurses were likely to misinterpret agitation as an expression of pain in
patients with agitated delirium in whom the pain was well controlled before and after the delirium38episode. Further, it is unclear whether available behavioral pain tools may assist in pain detection in
older adults during episodes of delirium. Only one pain assessment tool has been developed for use with
this particular patient population; however, initial testing of the tool was conducted in cognitively intact
39older adults undergoing orthopedic surgery and not in those with cognitive impairments.
Thus, the relationships between pain and delirium are complex and unclear. Although improved pain
treatment may reduce the occurrence of delirium in older adults, there is a gap in the literature
regarding assessment of pain in patients with delirium. It may not be possible to identify pain
de8nitively by behavioral presentation in patients with delirium and may require alternative
approaches to pain assessment, such as analgesic trial, addressed in later sections of this chapter.
Older adults have an increased prevalence of comorbid illness and trauma and account for more than
4060% of all ICU days. During episodes of severe critical illness, older people may lose the ability to
speak owing to an unconscious state, the presence of an endotracheal tube, or fatigue.
41Many older adults die in the ICU. However, patients able to report the ICU experience in retrospect
indicated that endotracheal intubation, mechanical ventilation, and the consequent inability to speak
41-43are extremely stressful events. Pain and the inability to speak were reported to be moderately to
extremely bothersome. Endotracheal suctioning is a particularly painful procedure, and the stressful
experience associated with the endotracheal tube was strongly associated with the subjects’
42experiencing spells of terror.
Sources of pain during episodes of critical illness include existing an medical condition, traumatic
injuries, the surgical/medical procedure, invasive instrumentation, blood draws, and other routine care
44-46such as turning, positioning, drain and catheter removal, and wound care. Adult patients
described the experience of pain in critical illness as a constant baseline aching pain with intermittent
45procedure-related pain that is experienced as sharp, stinging, stabbing, shooting, and awful pain.
Although most studies have been conducted with younger patients, it should be assumed that nonverbal
older adults also experience these sensations.
Identi8cation of pain in nonverbal older patients who are unable to communicate their pain and
discomfort owing to critical illness requires astute observational skill. Moreover, the complexity of
detecting pain is confounded by the overhanging threat of delirium that occurs in approximately 62%
25of older adults in the ICU.
The inability of nonverbal populations to communicate pain and discomfort represents a major barrier
to adequate pain assessment and treatment. The evidence indicates the urgent need to improve methods
of detecting and managing pain in these vulnerable populations and is addressed in the following
Assessment of pain is a critical component of a comprehensive approach to pain management in all
populations. The purpose of pain assessment is to detect the presence and source of pain, identify any
comorbidities requiring attention, determine the eEect of pain on function, and collect data on which to
6base individual treatment plans. Achievement of these goals is challenging in nonverbal older adults.
Nevertheless, general principles can guide approaches to pain identi8cation, measurement, and
continuous monitoring, as well as selection of speci8c pain assessment strategies in nonverbal older
adults.The American Society for Pain Management Nursing (ASPMN) recently published recommendations
47for pain assessment in nonverbal individuals. This comprehensive, hierarchical strategy includes 8ve
key principles to guide pain assessment in nonverbal populations: (1) obtain a self-report if at all
possible, (2) investigate for possible pathologies that could produce pain, (3) observe for behaviors that
may indicate pain, (4) solicit a surrogate report, and (5) use analgesics to evaluate whether pain
47management causes a reduction in the behavioral indicators believed to be related to pain. These
principles reDect a decision making process, illustrated in Figure 5–1, that may guide and support
health care clinicians and are discussed in greater depth in the following section.
Figure 5–1 Pain assessment in elders with severe cognitive impairment. *For example, grimacing,
guarding, combativeness, groaning with movement; resisting care; **for example, agitation, 8dgeting,
sleep disturbance, diminished appetite, irritability, reclusiveness, disruptive behavior, rigidity, rapid
blinking; †for example, toileting, thirst, hunger, visual or hearing impairment.
From Reuben DB, Herr KA, Pacala JT, et al. Geriatrics At Your Fingertips: 2007–2008 Edition. New York: The
American Geriatrics Society, 2007. Used with permission.
Obtain a Self-report
Attempts should be made to obtain a self-report of pain from all patients. The ability of cognitively
impaired patients to report their pain consistently and accurately varies widely across levels of cognitive
48impairment. Research indicates that individuals with mild and moderate dementia and even some
7,48-50with severe dementia are able to self-report. Even a limited yes/no response to a query regarding
pain presence is important information regarding the patient’s own pain experience.With increasing cognitive impairment, the ability to reliably use self-report instruments wanes.
Although no clear method has been identi8ed to address reliability in using self-report instruments,
51BuEum and colleagues described a Pain Screening Tool, an approach developed for evaluating
cognitive ability to reliably complete pain intensity scales. Patients are asked to provide a number from
0 to 3 and a word to describe their pain. After 1 minute of distracting conversation, the respondent is
asked to recall the number and the word. Patients receive one point each for being able to provide an
initial number and word and one half point each for recalling the number and the word. Only
respondents who score a three are identified as providing reliable pain reports.
Strategies that increase the likelihood of obtaining a self-report of pain from a cognitively impaired
individual may include use of a modi8ed verbal rating scale with a limited number of descriptors,
careful instruction on tool use and repetition, focus on the individual’s current pain rather than past
48,52pain experience, and adaptation of tools to compensate for possible sensory impairments.
However, despite these eEorts, many patients’ impairments will be severe enough to require alternative
approaches to assessment.
Search for Potential Causes of Pain
Pathologic conditions should be considered as a potential cause of pain and discomfort in the
assessment process. History and general physical evaluation, examination of any painful regions, as well
as consideration of any pain medication regimen provide essential information for clinical decisions.
Musculoskeletal and neurologic conditions are among the most common causes of pain in older adults
and should be given priority in the clinical examination. Moreover, evaluation of the patient’s cognitive
status is a crucial element of geriatric focused-pain assessment because both acute and chronic pain can
aEect cognition. When pain-associated pathologies are identi8ed, the presence of pain may be assumed
and appropriate pain intervention strategies should be implemented. Pain should be treated
1,47preemptively prior to initiation of any procedures known to cause pain. A change in behavior
should initiate a search for any acute problems as a source of pain or discomfort (e.g., pneumonia,
urinary tract infection, a recent fall). Detailed guidelines with recommendations for assessment of pain
6pathology in older adults are available.
Observe for Behaviors that May Indicate Pain
When older adults are unable to communicate the presence of pain owing to cognitive impairments,
unconsciousness, or severe critical illness, reliance on external signs of pain, such as nonverbal
behaviors and physiologic changes, becomes a necessary approach to pain detection. The American
2Geriatrics Society (AGS) Panel on Persistent Pain in Older Persons compiled a comprehensive list of
nonverbal behaviors observed in older adults with cognitive impairment with six categories of pain
behavioral indicators: facial expressions, verbalizations/vocalizations, body movements, changes in
interpersonal interactions, changes in activity patterns or routines, and mental status change (see Table
5–2). This framework provides a valuable resource for evaluating the relevance and comprehensiveness
53of behaviors included on a particular behavioral pain tool for use with older adults.
Observational approaches to pain assessment rely on interpretation of behaviors. The inherent
subjectivity involved in observational approaches represents challenges to the reliability and validity of
pain assessments. Important issues for consideration when using behavioral observation to detect pain
or when selecting a behavioral pain tool are summarized in Table 5–3. In the following section, we
provide recommendations that may maximize observational pain assessment approaches in nonverbal
older adults.
Table 5–3 Key Issues in Behavioral Pain Assessment in Older Adults with Cognitive ImpairmentIssue Key Considerations
Specific vs.
• Specific behaviors are obvious and commonly observed in pain states (e.g. facialsubtle
2expressions, verbalizations/vocalizations, body movements)behaviors
• Subtle behaviors reflect change from usual individual behavioral pattern and are
less obvious pain indicators (e.g., changes in interpersonal interactions, activity
2patterns or mental status)
• Subtle behaviors require interpretation and validation that pain is the etiology
• Specific, obvious indicators may be observed directly; no prior history with theobservation
patient is requiredvs. surrogate
report • Subtle behaviors of change from baseline require reassessment over time by
individuals familiar with the patient
• Use of surrogate reporting requires caution due to evidence of disagreements
between self-report of pain by cognitively impaired individuals and proxy
• Patient self-report and proxy report of pain severity show increasing disagreementpresence vs.
50with increasing severity of cognitive impairmentseverity
• Evidence documents surrogate/proxy ability to recognized pain presence but not
84,86,88• Professional caregivers tend to underestimate patient pain severity
• Family members tend to overestimate patient pain severity and level of
• A behavioral pain tool score is not the same as a pain intensity rating; pain
90behavior tool score and score on pain intensity ratings should not be compared
• A comprehensive indicator set including obvious and less obvious pain behaviorsvs. specificity
91increases sensitivity of behavioral tools to detect pain when present
• A narrow indicator set with only obvious indicators increases specificity of
behavioral tools to rule out pain when pain is not present, but are less sensitive in
91detecting pain in those with less obvious pain presentation
Screening vs.
• Behavioral pain assessment may assist in screening for presence of pain, but doesdiagnostic
not provide diagnostic certainty regarding exact nature and cause of possible pain tocertainty
64-6668guide treatment
• In situations in which uncertainty prevails, an empirical analgesic trial is warranted
1,6,47as a pain assessment strategy
Behavioral indicators for pain assessment must be appropriate to the patient population, setting, andtype of pain problems encountered. The shorter behavioral pain tools tend to be direct observation–
focused including speci8c behaviors that may be observed in a direct encounter by trained observers
54,55(e.g., grimacing, guarding, restlessness, moaning, 8ghting the ventilator). The patient may be
observed for a speci8ed period and activity for the presence or absence, intensity, or frequency of pain
54,56behaviors. Shorter behavioral tools require no previous history with the patient, an advantage in
the acute care setting. Longer pain scales are more comprehensive including more subtle behavioral
indicators in addition to those commonly observed. Items such as changes in activity patterns or
routines, interpersonal interactions, or mental status require involvement of family and caregivers
familiar with the patient’s baseline or typical behaviors. Thus, longer tools may be more appropriate in
the long-term care (LTC) setting in which patients may be observed over time while performing
everyday activities.
With chronic pain states, changes in physiologic indicators are often not observed. In acute pain
situations, physiologic and behavioral indicators may increase temporarily, but these changes may be
attributed to underlying physiologic conditions and medications. Thus, changes in vital signs are not
reliable as single indicators of pain, but changes in physiologic indicators (e.g., blood pressure, pulse,
oxygen saturation) should be considered a cue to begin further assessment for pain or other stressors.
57,58Moreover, an absence of increased vital signs does not indicate an absence of pain.
The conditions of behavioral observation are also important to ensure reliability of assessments.
Observation of behaviors should occur during movement or activity that is likely to elicit a pain
response if pain is present. Studies have demonstrated that observation of pain behaviors at rest is
misleading and can result in false judgments that pain is absent, leading to underdetection and
18,54,59,60undertreatment. Moreover, serial observations should be performed under similar
circumstances (e.g., time of day, activity performed) to ensure comparability of behavioral pain
assessments over time.
Solicit Support of Surrogate Reporters
In the absence of pain self-report, surrogate observation is an important source of information. Family
members or others who know the patient well (e.g., spouse, child, caregiver) should be encouraged to
provide information regarding usual and past behaviors as well as to assist in the identi8cation of
subtle, less obvious changes in behavior that may indicate pain presence. In LTC, the certi8ed nursing
assistant is a key health care provider who has been shown to be eEective in recognizing the presence of
61,62pain. In settings in which health care providers do not have a history with the patient, family
members are likely to be the caregivers with the most familiarity with typical pain behaviors or changes
in usual activities that might suggest pain presence. A family member’s report of their impression of a
patient’s pain and response to an intervention should be included as one component of pain assessment
that encompasses multiple sources of information. When engaging multiple care providers and
surrogates in pain screening procedures, training is important to safeguard the reliability of behavioral
observations. Moreover, when introducing new behavioral tools to the clinical setting, interrater
reliability between caregivers should be established initially as well as on a regular basis to calibrate
observations, thus reducing subjectivity and the potential for bias associated with this method.
Conduct an Analgesic Trial
If, after following the initial steps in this multifaceted approach to pain assessment, behaviors persist
that may indicate pain, an analgesic trial is warranted. The underlying supposition is that any reduction
in behaviors after analgesic intervention is related to improved pain control. Early unblinded trials
63 64provided preliminary support for this approach. BuEum and coworkers did not demonstrate
signi8cant changes in agitated behavior believed to be pain related in persons with advanced dementia;
however, the acetaminophen dose was only 1500 mg/day. In a randomized, controlled trial (RCT)
65evaluating low-dose opioids in persons with dementia, Manfredi and associates reported decreasedagitation in the over-85 age group and suggested that less response in the younger old group could be
related to low dosing of analgesic. In a recent double-blind crossover RCT with patients with dementia
66receiving 3000 mg/day of acetaminophen, Chibnall and colleagues demonstrated increased levels of
social activity and interaction compared with the times the patients were receiving placebo. An
analgesic trial is an integrated component of the Serial Trial Intervention (STI), a clinical protocol
67developed by Kovach and colleagues, that uses a systematic method for assessing and treating
potential pain-related behaviors in patients with severe dementia. A recent RCT of the STI demonstrated
signi8cantly less discomfort and behavioral symptoms returning to baseline more frequently in the
treatment group and has been shown to be eEective in increasing recognition and treatment of pain in
68persons with dementia. Although an analgesic trial is a promising approach, selecting and titrating
analgesics for this purpose have not been clearly explicated or studied. The use of an analgesic trial as a
means to evaluate pain as the cause of potential pain-related behaviors requires further investigation
but is likely an important step in the process of recognizing and validating pain in those presenting with
atypical pain behaviors.
This section has outlined key components of a comprehensive approach to pain assessment in nonverbal
older adults. A multifaceted approach is recommended that combines direct observation of behaviors,
family/caregiver input, and evaluation of response to treatment. A standardized behavioral pain tool
may be used as one component of a comprehensive approach to pain assessment and is addressed in the
following section.
Since the late 1990s, a number of standardized tools for pain assessment based on observation of
behaviors have been developed for use with nonverbal older adult populations. Several reviews of
53,69-72available tools have indicated that, although there are tools with potential, currently no tool
has suO ciently strong reliability and validity to support recommendation for broad adoption in clinical
practice. Moreover, reviews have called for further tool testing in larger samples and/or in diverse
53clinical settings. In an earlier comprehensive review, Herr and associates critiqued 10 tools for use
with nonverbal adults with advanced dementia based on published reports of psychometric data. Since
the publication of this review, some tools have undergone further testing and development. In the
following discussion, a selection of tools is presented with updated critiques. Further, we have included
two recently developed tools for use with critically ill adult patients who are unconscious and/or
intubated that have not previously been critiqued for relevance, reliability, and validity for use with this
patient population. Table 5–4 provides an overview of characteristics of the selected tools with
presentation of tool items and scoring range, reliability, validity, and clinical utility.
Table 5–4 Characteristics of Selected Behavioral Pain Assessment Tools for Nonverbal Older Adults with
Dementia or Severe Critical Illness (Unconscious/Intubated)18,54The Checklist of Nonverbal Pain Indicators
The Checklist of Nonverbal Pain Indicators (CNPI), developed to measure pain in cognitively impaired
older adults, includes six conceptually sound behavioral items commonly observed in direct observation
situations. Initial tool testing supports the reliability and validity of this tool for use in acute care,
although internal consistencies were low, suggesting a need for further testing. In a tool evaluation in
Norwegian nursing homes, the test-retest and interrater reliabilities reported were low to moderate when
administered by various categories of nursing personnel as an element of daily care, and moreover,
73 91concurrent validity was supported. In another recent study in LTC, sensitivity of the CNPI was
moderate, while at the same time, nearly half the residents who reported having pain showed no pain
behaviors on the CNPI, thus giving rise to concerns about the ability of the tool to detect pain in those
unable to report. Because the CNPI lacks indicators of subtle behaviors, the tool’s ability to detect pain
in those with less obvious behavioral presentation is questioned. Thus, this tool may be more
appropriate for use in acute care. However, additional testing in larger and more acute care samples is
74The Doloplus 2The Doloplus 2 is a French tool developed for multidimensional assessment of pain in nonverbal older
adults. Psychometric evaluations are available based on French-, Dutch-, and Norwegian-speaking
populations, but not on English-speaking ones. The Doloplus 2 addresses many key indicators noted in
the literature and AGS Guidelines. Doloplus reDects the progression of experienced pain, not current
pain experience; thus, intrarater and interrater reliabilities of the tool represent a particular challenge
and have not yet been adequately established. Although internal consistencies for the total scale and the
psychomotor reactions subscale were strong, reliabilities for somatic reactions and psychosocial reactions
75subscales were low. Moreover, a Norwegian study demonstrated that the four most informative tool
items explained 68% of the variance of the expert score, with the psychosocial reactions subscale
76 49,75,76contributing little to the tool. Thus, despite evidence to support validity, there is indication of
need for a tool revision. Moreover, although clinicians report the ctool manual is clear, in clinical
75,76testing, nurses reported that the tool is difficult to score and interpret.
77The Pain Assessment Checklist for Seniors with Severe Dementia
The Pain Assessment Checklist for Seniors with Severe Dementia (PACSLAC), developed by a Canadian
team, is a conceptually sound comprehensive checklist of pain behaviors that addresses all six pain
behavioral categories included in the AGS Guidelines. In preliminary testing, the PACSLAC showed
initial reliability and validity based on retrospective judgments. In recent prospective testing of a Dutch
75version of the tool, interrater and intrarater reliabilities were high. The tool includes 60 behavioral
items; however, nearly half the items were not observed in over 90% of the study subjects, suggesting a
need for item reduction. Moreover, although internal consistency for total tool score was good, results
for subscale scores were poor to moderate, suggesting a need for tool revision. PACSLAC also showed
good construct and congruent validity and was rated the most preferred behavioral pain tool by Dutch
nurses. Thus, the Dutch research team found the PACSLAC to be the most promising tool for further
The Pain Assessment Checklist for Seniors with Severe
The PACSLAC—Dutch-Revised (PACSLAC-D-Revised) is a 24-item preliminary tool with three subscales
derived from the original PACSLAC based on factor analysis. Internal consistencies of the total tool and
revised subscales are good. Moreover, the reduced version of the scale correlated highly with the
original tool, suggesting that validity is retained. However, further prospective, con8rmatory testing in
an independent sample is needed.
78The Pain Assessment in Advanced Dementia Scale
The Pain Assessment in Advanced Dementia (PAINAD) scale was developed as a short, easy-to-use
observation tool for behavioral pain assessment in nonverbal older adults with advanced dementia.
79 75Originally developed in English, the PAINAD has been translated and tested in Italian, Dutch, and
80 75,78-80 75,79,80German. Although interrater and test-retest reliabilities have been supported,
75internal consistency is only moderate, with the breathing item scoring persistently low. Evidence
currently supports several types of validity. However, despite mounting evidence of reliability and
validity, issues persist. The PAINAD attempts to measure severity based on scoring of behaviors that has
not been substantiated in the literature. Moreover, in clinical testing, nurses report experiencing the
75PAINAD as too concise, with too few pain cues included. In one study, raters did not use the breathing
75item in painful situations in over 80% of participants with pain. In another study, nurses expressed
80uncertainty regarding the consolability item. Thus, the limited number of items restricts the ability of
the PAINAD to detect pain in persons with dementia with more subtle behavioral presentation.81Behavioral Pain Scale
The Behavioral Pain Scale (BPS) is a French tool developed for critically ill, sedated adult patients
undergoing mechanical ventilation. Initial reports of tool testing in trauma and postoperative ICUs in
81 82France and Morocco appear to provide initial support for reliability and validity; however, results
are largely based on the total number of observations rather than on individual patients. Initial
validation studies were conducted with younger adults; thus, testing in older adult populations is
needed. An English version of the BPS was tested in Australia in unconscious medical and surgical ICU
83patients, including some older patients (median age 64 yr, range 16–82). Reported reliabilities were
variable, suggesting a need for further testing under more tightly controlled conditions. Data were
skewed toward the lower end of the BPS, which may indicate inaccurate scaling of items. Patients were
not assessed for delirium in any of these three BPS studies. Thus, further testing of the BPS is needed to
establish reliability and validity using patients as the unit of analysis, and moreover, testing in older
adults is needed.
55Critical Care Pain Observation Tool
The Critical Care Pain Observation Tool (CPOT) is a French tool developed by a Canadian team for
assessment of pain behaviors in critically ill patients unable to communicate verbally. The CPOT
attempts to measure pain intensity via behavioral observation, which has not been substantiated in the
literature. Initial tool testing was conducted in cognitively intact adult surgical patients with no delirium
while unconscious, conscious, intubated, and after extubation. Internal consistency was not reported,
and interrater reliability was only moderate; thus, further testing is necessary to establish reliability.
Initial tool validity was supported. Although this tool shows promise, tool testing in critically ill older
adult samples as well as testing in English-speaking populations are needed.
This review demonstrates progress is being made in the development and validation of behavioral pain
tools for use with nonverbal older adults. Yet, despite advances, no single pain behavioral tool has been
shown to be superior for use with older adults who are unable to communicate verbally owing to
dementia or to unconscious state and/or intubation. Continued and concerted eEort is needed to
develop and validate tools for nonverbal populations.
Pain is an important health problem for nonverbal older adults with dementia and delirium and during
episodes of severe critical illness requiring appropriate strategies for these vulnerable populations. A
comprehensive approach to assessment is advocated, including multiple sources of information to
ensure a valid and reliable basis on which to make treatment decisions. Behavioral observation and
surrogate report are essential components of a multifaceted approach to assessment that may include
standardized behavioral pain tools. Although some currently available tools for behavioral assessment in
nonverbal older adults show promise, there is currently no single tool with suO cient validity and
reliability to warrant recommendation for broad adoption in clinical practice.
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63. Kovach CR, Weissman DE, Griffie J, et al. Assessment and treatment of discomfort for people with
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67. Kovach CR, Noonan PE, Griffie J, et al. Use of the Assessment of Discomfort in Dementia protocol. Appl
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78. Warden V, Hurley AC, Volicer L. Development and psychometric evaluation of the Pain Assessment in
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80. Schuler MS, Becker S, Kaspar R, et al. Psychometric properties of the German Pain Assessment in
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81. Payen JF, Bru O, Bosson JL, et al. Assessing pain in critically ill sedated patients by using a behavioral
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82. Aissaoui Y, Zeggwagh AA, Zekraoui A, et al. Validation of a behavioral pain scale in critically ill,
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84. Manfredi PL, Breuer B, Meier DE, Libow L. Pain assessment in elderly patients with severe dementia. J
Pain Symptom Manage. 2003;25:48-52.
85. Cohen-Mansfield J, Creedon M. Nursing staff members’ perceptions of pain indicators in persons with
severe dementia. Clin J Pain. 2002;18:64-73.
86. Cohen-Mansfield J, Lipson S. Pain in cognitively impaired nursing home residents: how well are
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87. Horgas AL, Dunn K. Pain in nursing home residents. Comparison of residents’ self-report and nursing
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88. Cohen-Mansfield J. Nursing staff members’ assessments of pain in cognitively impaired nursing home
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89. Cohen-Mansfield J. Relatives’ assessment of pain in cognitively impaired nursing home residents. J Pain
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90. Pasero C, McCaffery M. No self-report means no pain-intensity rating. Am J Nurs. 2005;105:50-53.
91. Jones KR, Fink R, Hutt E, et al. Measuring pain intensity in nursing home residents. J Pain Symptom
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92. Zwakhalen SMG, Hamers JPH, Berger MPF. Improving the clinical usefulness of a behavioural pain
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93. Lane P, Kuntupis M, MacDonald S, et al. A pain assessment tool for people with advanced Alzheimer’s
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SUGGESTED READINGSAmerican Geriatric Society (AGS) Panel on Persistent Pain in Older Persons. The management of persistent
pain in older persons. J Am Geriatr Soc. 2002;50:S205-S224.
Closs SJ, Barr B, Briggs M, et al. A comparison of five pain assessment scales for nursing home residents
with varying degrees of cognitive impairment. J Pain Symptom Manage. 2004;27:196-205.
Hadjistavropoulos T, Herr K, Turk DC, et al. An interdisciplinary expert consensus statement on assessment
of pain in older persons. Clin J Pain. 2007;23:S1-S43.
Herr K, Bjoro K, Decker S. Tools for assessment of pain in nonverbal older adults with dementia: a
state-ofthe-science review. J Pain Symptom Manage. 2006;31:170-192.
Herr K, Coyne PJ, Key T, et al. Pain assessment in the nonverbal patient: position statement with clinical
practice recommendations. Pain Manage Nurs. 2006;7:44-52.
McNicoll L, Pisani MA, Zhang Y, et al. Delirium in the intensive care unit: occurrence and clinical course in
older patients. J Am Geriatr Soc. 2003;51:591-598.
Proctor WR, Hirdes JP. Pain and cognitive status among nursing home residents in Canada. Pain Res
Manage. 2001;6:119-125.
Scherder E, Oosterman J, Swaab D, et al. Recent developments in pain in dementia. BMJ.
Zwakhalen SM, Hamers JP, Berger MP. The psychometric quality and clinical usefulness of three pain
assessment tools for elderly people with dementia. Pain. 2006;126:210-220.&


Chapter 6
Howard S. Smith, Misha-Miroslav Backonja, Marco Pappagallo, Charles E.
Neuropathic pain (NP) presents a puzzle to patients and a challenge to clinicians because it manifests
simultaneously with seemingly contradictory positive (pain) and negative (lack of sensation) sensory
phenomena. The lack of a conceptual framework within which progress in the science of pain can
translate into improvement in clinical care and vice versa presents additional di culty when addressing
1Derasari stated that the main impact of e" ective taxonomy is the framework for the interpretation of
the di" erences and similarities in living organisms in light of comparative genetics, biochemistry,
physiology, embryology, behavior, and etiology. Commonly accepted terminology and classi cations of
pain have recently come under scrutiny as our understanding of central and peripheral
pathophysiologic processes has continued to grow. One key example has been NP. Simple distinctions
such as that of nociceptive pain versus NP are woefully inadequate. The term nociceptive pain refers to
pain that is transmitted under laboratory conditions of pain stimulation that do not truly exist in any
clinical situation. More importantly, the lack of speci city of the term as proposed by the International
Association for the Study of Pain (IASP) is contradictory to the preferred approach—the
mechanismbased diagnosis and treatment of all painful conditions.
NP remains a signi cant challenge to diagnose and treat e" ectively. Perhaps, this is in part related to
the di culty in de ning NP. The IASP de ned NP as “pain initiated or caused by a primary lesion or
dysfunction in the nervous system.”
2Controversy exists regarding the de nition of NP and what it entails. Max argued for removal of the
words “or dysfunction” from the IASP de nition and proposed that the de nition for NP be “pain
3initiated or caused by a primary lesion of the nervous system.” Conversely, Jensen and coworkers
opined that going back to a pure neuroanatomic description of NP overlooks the plasticity of the
nervous system and its continuous modulation, which may change after activation or injury. In 2002,
4Merskey noted that without the word “dysfunction” in the de nition of NP, the entity of trigeminal
neuralgia may require two subcategories, one neuropathic with a de nable lesion and one not. In 2006,
Gary Bennett suggested that given the present level of understanding, a clean separation between
in: ammatory pain and NP may not be realistic in many patients, and a satisfying de nition of NP may
not be currently possible.
A clinically acceptable de nition of NP is vitally important because e" ective treatment of NP remains
a challenge and the number of patients with NP is signi cant and growing. A group consisting of
neurologists, neuroscientists, clinical neurophysiologists, and neurosurgeons established a task force in
collaboration with the IASP Special Interest Group on Neuropathic Pain (NeuPSIG) and put forth a
5revised definition and grading system for NP.
5Treede and associates proposed that NP be rede ned/reworded as “pain arising as a direct
consequence of a lesion or disease a" ecting the somatosensory system.” Peripheral NP and central NP
are proposed to refer to lesions/disease of the peripheral nervous system (PNS) and central nervous&

5system (CNS), respectively.
The NP grading system is used to decide on the level of certainty with which the presence or absence
5of NP can be determined in an individual patient. The grading of certainty for the presence of NP
consists of
Definite NP: all (1–4).
Probable NP: 1 and 2, plus either 3 or 4.
Possible NP: 1 and 2, without confirmatory evidence from 3 or 4.
The levels “de nite” and “probable” indicate that the presence of this condition has been established.
The level “possible” indicates that the presence of this condition has not yet been established, which
should instigate additional investigations in this patient, either immediately or during follow-up. If a
patient does not ful ll the criteria for any of these three levels, it is considered unlikely that this patient
5has NP.
The criteria to be evaluated for each patient are
1. Pain with a distinct neuroanatomically plausible distribution.*
2. A history suggestive of a relevant lesion or disease affecting the peripheral or central somatosensory
3. Demonstration of the distinct neuroanatomically plausible distribution by at least one confirmatory
§54. Demonstration of the relevant lesion or disease by at least one confirmatory test.
5Treede and associates pointed out that controversy over whether diseases such as complex regional
pain syndrome I constitute NP will not be resolved by their proposed de nition. However, it is
conceivable that future tools/research may help sort this out. This new de nition and criteria will likely
yield a lower sensitivity but higher specificity than the IASP definition for the identification of NP.
Although the precise incidence of NP in the general population is unknown, it appears that NP exists
in a signi cant portion of the population and, thus, presents a major clinical problem. Torrance and
colleagues mailed a questionnaire (which included the Self-complete Leeds Assessment of Neuropathic
Symptoms and Signs [S-LANSS] and the Neuropathic Pain Scale [NPS]; described later) to six family
practices in three U.K. cities and found that chronic pain with neuropathic features appears to be more
common in the general population than previously suggested.
6Multiple measurement tools exist to assess the intensity of pain, however. In 1997, Galer and Jensen
published the NPS in e" orts to assess the intensity of, speci cally, NP. The NPS is essentially a
measurement tool of NP severity. The NPS was designed to assess distinct pain qualities associated with
6 7NP. In 2005, Jensen and colleagues proposed that the NPS may have utility in assessing changes in
pain qualities after analgesic treatments (e.g., lidocaine 5% patch).
NP presents some unique issues, and it may be di cult at times to correctly recognize the
8neuropathic qualities of various painful complaints by patients. In 2007, Bennett and coworkers
reviewed ve screening tools used to identify NP (with up to 80% sensitivity and speci city) (Table 6–
1). It can be appreciated that the rst three items (“pricking, tingling, pins and needles,” “electric
shocks or shooting,” and “hot or burning”) are present in all tools, with the next two items (“numbness”
and “pain evoked by light touching”) present in 80% of the tools in Table 6–1.&
Table 6–1 Comparison of Items within Five Neuropathic Screening Tools*
Leeds Assessment of Neuropathic Symptoms and Signs
9In 2001, Bennett published the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), which
contains ve symptom and two clinical examination items and is easy to score within clinical settings.
10In 2005, Bennett and associates validated a self-report tool, the S-LANSS. The original LANSS was
developed in a sample of 60 patients with chronic nociceptive pain or NP and validated in a further
sample of 40 patients. Sensitivity and speci city in the latter group were 85% and 80%, respectively,
compared with clinical diagnosis.
The LANSS has subsequently been tested and validated in several settings. Although the LANSS was
11not designed as a measurement tool, Khedr and colleagues showed sensitivity to treatment effects.
Douleur Neuropathique 4 Questions
12In 2005, Bouhassira and coworkers published a comparison of pain syndromes associated with
nervous or somatic lesions utilizing a new NP diagnostic questionnaire. The French Neuropathic Pain
Group developed a clinician-administered questionnaire called DN4, which stands for “douleur
neuropathique 4 questions” (i.e., “neuropathic pain four questions,” in French). The DN4 was validated
in 160 patients with either NP or nociceptive pain. The most common etiologies of NP (n = 89) were
traumatic nerve injury, postherpetic neuralgia (PHN), and poststroke pain. Nonneurologic conditions
included osteoarthritis, in: ammatory arthropathies, and mechanical low back pain. It consists of 7
items related to symptoms and 3 related to clinical examination. A score of 1 is given to each positive
item and a score of 0 is given to each negative item. The total score is the sum of the 10 items. The DN4
is easy to score, and a total score of 4 or more out of 10 suggests NP. The DN4 showed 83% sensitivity
and 90% speci city when compared with clinical diagnosis in the development study. The rst 7
sensory descriptors (based solely on patient interview) can be used as a self-report questionnaire with
similar results (Box 6–1). DN4 is complementary to the NPS or the Neuropathic Pain Symptom
13Inventory (NPSI). In 2004, Bouhassira and associates published the NPSI for the evaluation of
di" erent symptoms and dimensions of NP. The nal version of the NPSI includes 10 descriptors (plus 2
temporal items) that allow discrimination and quanti cation of ve distinct clinically relevant&
dimensions of NP syndromes. It has been suggested that NPSI is particularly suitable to assess treatment
From Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or
somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain
Neuropathic Pain Questionnaire
14In 2003, Krause and Backonja published the Neuropathic Pain Questionnaire (NPQ), which consists
of 12 items, including 10 related to sensations or sensory responses and 2 related to a" ect. It was
developed in 382 patients with a broad range of chronic pain diagnoses. The discriminant function was
initially calculated on a random sample of 75% of the patients and then cross-validated in the
remaining 25%. The NPQ demonstrated 66% sensitivity and 74% speci city compared with clinical
15diagnosis in the validation sample. Backonja and Krause also published a short form of the NPQ,
which maintained similar discriminative properties with only 3 items: (1) positive sensory phenomena
(“increased pain due to touch”); (2) negative sensory phenomena (“numbness”); and (3) phenomena
suggestive of paresthesia and dysesthesia (“tingling”).
16In 2005, Freynhagen and colleagues published the screening tool referred to as painDETECT, which
was developed and validated in German. painDETECT incorporated an easy-to-use, patient-based
(selfreport) questionnaire with nine items that do not require a clinical examination. There are seven
weighted sensory descriptor items (“never” to “very strongly”) and two items relating to the spatial
(“radiating”) and temporal characteristics of the individual pain pattern. The painDETECT
questionnaire (PD-Q) was developed in cooperation with the German Research Network on Neuropathic
Pain; validated in a prospective, multicenter study of 392 patients with either NP (n = 167) or&
nociceptive pain (n = 225); and subsequently applied to a population of roughly 8000 patients with
low back pain. The tool correctly classi ed 83% of patients to their diagnostic group with a sensitivity
of 85% and a specificity of 80%. It is also available in English.
ID Pain
17In 2006, Portenoy published the ID Pain, which consists of ve sensory descriptor items and one item
relating to whether pain is located in the joints (used to identify nociceptive pain). It also does not
require a clinical examination (Table 6–2). The tool was developed in a multicenter study of 586
patients with chronic pain of nociceptive, mixed, or neuropathic etiology and validated in a multicenter
study of 308 patients with similar pain classi cations. The tool was designed to screen for the likely
presence of a neuropathic component to the patient’s pain.
Table 6–2 ID Pain Questionnaire
Rights were not granted to include this table in electronic media. Please refer to the printed book.
From Portenoy R. Development and testing of a neuropathic pain screening questionnaire: ID Pain. Curr Med
Res Opin 2006;22:1555–1565.
In the validation study, 22% of the nociceptive group, 39% of the mixed group, and 58% of the
neuropathic group scored above 3 points, the recommended cut-off score.
Traditionally, neurologic research and practice have followed a distinction between the PNS and the
CNS, and in many regards, this division has served the eld of neurology very well—for example,
clearly distinct clinical courses have been mapped for demyelinating disorders of the PNS (e.g.,
in: ammatory demyelinating polyradiculoneuropathy) and of the CNS (e.g., demyelinating disorder of
multiple sclerosis), although both can be progressive and, as part of presentation, have chronic pain.
Conversely, pain does not necessarily respect that distinction between the PNS and the CNS because any
time a painful event occurs, the whole system is activated, from nociception, to modulation, to
18perception—leading to a reaction to pain. Petersen and coworkers shed light on the fact that NP, even
though it may appear “centralized,” may still exhibit ongoing nociceptive input from the periphery. A
further conceptual challenge for NP is that, although the clinical course and expression of the disorder
are under the in: uence of the underlying disease process (e.g., painful diabetic peripheral neuropathy&
vs. spinal cord injury), most of its phenomenologic manifestations including ongoing pain, pain
paroxysms, and various types of hyperalgesia are frequently similar, regardless of whether injury occurs
to the PNS or the CNS. The nature and the extent of the nervous system injury and the natural course of
repair that follows with involvement of in: ammatory processes all add to the complexity and dynamic
nature of NP in each particular case.
NP has its own signature characteristics. There are books (Pappagallo M [ed]. The Neurological Basis
of Pain. New York: McGraw-Hill, 2005), journals (The Journal of Neuropathic Pain and Symptom
Palliation), and groups (the NeuPSIG of the IASP) largely devoted speci cally to NP. Modern
neuroimaging methods (position-emission tomography [PET] and functional magnetic resonance
imaging [fMRI]) have overall indicated that acute physiologic pain and NP have distinct, although
overlapping, brain activation patterns but that there is no unique “neuropathic pain matrix” or
19“allodynia network.”
The distinction between in: ammatory pain and NP in many regards is arbitrary, but on a practical
level, the distinction may have direct implications for the diagnostic steps and therapeutic planning in
addition to the natural course of the disease for each type of pain. Insult or irritation of nerves may
promote in: ammation and in: ammation may a" ect neural function. In fact, even in the basic sciences,
various animal models may not be “black and white.” Although the air pouch model appears to be
largely inflammatory and the chronic constriction injury model appears largely neuropathic, injection of
formalin into the rodent hind paw (traditionally considered an in: ammatory model) may actually be
more of a “mixed picture” and the speci c type of insults appears to be somewhat dose-dependent. The
systematically obtained clinical and experimental data would then determine whether a particular pain
disorder is neuropathic or whether it presents a transitional form (i.e., at the overlapping borders of NP
and other pain processes) (Fig. 6–1).
Figure 6–1 Spectrum of pathophysiologic mechanisms, neuropathic and in: ammatory, and their
in: uence on common painful disorders. CIDP, chronic in: ammatory diabetic polyneuropathy; CRPS,
complex regional pain syndrome; OA, osteoarthritis; PDN, painful diabetic neuropathy; PHN,
postherpetic neuralgia; RA, rheumatoid arthritis.
Conventional older classi cations have divided persistent pain into two mutually exclusive categories:
nociceptive and neuropathic. Clinicians later realized that in practice, pain complaints were not strictly
black and white, and they considered a categorization of persistent pain as (1) neuropathic, (2)
nonneuropathic (e.g., nociceptive), or (3) nonneuropathic with neuropathic
features/qualities/characteristics or a neuropathic component. This third category refers to a single pain
complaint that contains a mix of nonneuropathic pain with a neuropathic component.
20Rasmussen and associates examined whether symptoms and signs cluster in patients with
increasing evidence of NP. They used three categories of NP (“de nite,” “possible,” and “unlikely”)
based on detailed sensory examination and found a considerable overlap of symptoms and signs&
21between the categories, using the Short-form McGill Pain Questionnaire (SF-MPQ).
Distinguishing NP from nonneuropathic pain in a speci c patient’s complaint is an interesting
challenge because in many patients there is a likely mix. A single pain complaint from a patient may
represent a fusion or mesh of NP and in: ammatory pain. Attempts to “tease out” “how much” (if any)
of the pain complaint is neuropathic in nature may potentially be worthwhile because it may a" ect
medical decision making regarding the planning of treatment strategies.
22Backonja and Stacey evaluated NP relative to overall pain rating. Intensity of symptoms as rated by
NPQ and NPS items varied widely, with the least intense being “itch and cold sensation” on NPS and
“heat and emotional upset” on NPQ. The most intense ratings were “unpleasant and sharp” on NPS and
“distressing and stabbing” on NPQ (Fig. 6–2).
Figure 6–2 Intensity of neuropathic pain symptoms as rates on the Neuropathic Pain Questionnaire
(NPQ) and the Neuropathic Pain Scale (NPS).
Reproduced from Backonja MM, Stacey B. Neuropathic pain symptoms relative to overall pain rating. J Pain
23Smith and colleagues sent the S-LANSS questionnaire to 6000 adults from general practices in the
United Kingdom, along with chronic pain identi cation and severity questions, the Brief Pain Inventory
(BPI), the NPS, and the SF-MPQ general health questionnaires.
The chronic Pain of Predominantly Neuropathic Origin (POPNO) group reported higher pain severity
and had signi cantly poorer scores for all interference items of the BPI than those with chronic pain
23(non-POPNO). Mean scores from the NPS were also signi cantly higher for the chronic POPNO group
23reporting the worst health. After adjusting for pain severity, age, and sex, the chronic POPNO group
was still found to have poorer scores than the non-POPNO group in all domains of the SF-MPQ and all
23interference items in the BPI, indicating poorer health and greater disability. This study supports the
importance of identifying NP in the community and the need for multidimensional management&

23strategies that address all aspects of health.
23,24Postal surveys were carried out in large community samples from the United Kingdom and
25France in attempts to gain information regarding the epidemiology of NP in the general population.
Although di" erent NP questionnaires were used (i.e., S-LANSS in the United Kingdom and DN4 in
France), similar estimates of the prevalence of chronic pain with neuropathic characteristics were
26reported in the general population, around 7% to 8%. Interestingly, these population-based studies
showed that the subset of respondents with NP features had several associated clinical characteristics
that di" ered from other respondents with chronic pain, even after controlling for pain severity. These
characteristics include signi cantly worse quality of life, greater interference from pain, and pain of
26longer duration.
One limitation inherent to this approach is the lack of direct information regarding the etiology of
pain. In other words, how sure can we be that a positive responder to a postal screening tool would be
27diagnosed with NP if seen by a pain specialist in a clinic? Weingarten and coworkers addressed this
very question and reported on a community validation study of the S-LANSS in an issue of Pain.
27Weingarten and coworkers mailed a short questionnaire that included questions on pain and,
10speci cally, the S-LANSS to nearly 6000 community adults and received over 3500 replies. A
subsample of these respondents were invited for clinical assessment, and nally, a comparison was
26made between clinical assessment and responses to S-LANSS after a gap of 3 to 12 months.
27Weingarten and coworkers asked subjects only for “any pain in the last 3 months as opposed to pain
26lasting for more than 3 months.” The prevalence of NP derived from the survey of Weingarten and
27 24coworkers (8.8%) is very close to that reported by Torrance and associates.
Patient’s symptoms remain the cornerstone of pain assessment; however, patients’ complaints should
not be the sole determinant in categorizing NP. NP needs to be carefully assessed by trained pain
specialists, starting with a complete and thorough history and physical examination. This would include
assessing mechanical and thermal hyperalgesia/allodynia as well as a detailed, more traditional
neurologic examination. The combination of history, physical examination, and ancillary con rmatory
testing, although providing enough information to categorize NP based on the criteria of Treede and
5associates, is not su cient to precisely dissect all patient’s pain complaints into neuropathic,
nonneuropathic, or mixed. Ideally, a valid speci c tool for the examination of patients with chronic
pain will be developed that will allow the examiner at the conclusion to be able to accurately predict
whether or not NP is present. Or perhaps testing may be developed that could be used in conjunction
with data from the history and physical examinations to aid in the identification of an NP component.
Furthermore, when appropriate, this information may be supplemented with various laboratory
testing, imaging, electrodiagnostic testing, quantitative sensory testing (QST), as well as speci c testing
of the skin such as provocative or challenge testing, assessing whether various agents (e.g., capsaicin)
exacerbate, alleviate, or do not a" ect preexisting spontaneous pain, and analysis of skin punch biopsies.
In addition, the future information from PET imaging or fMRI may be useful to supplement these data.
Over the last 2 decades, QST has been developed to complement traditional neurologic bedside
28examination in the analysis of somatosensory aberrations. This approach, derived from experimental
psychophysics, consists of measuring the responses (i.e., nonpainful sensations and pain) evoked by
29mechanical and thermal stimuli, the intensity of which is controlled by automated devices.
QST is based on precise de nition of the stimulus properties (modality, intensity, spatial, and
temporal characteristics), analysis of the quality of evoked sensation, and quanti cation of its
29intensity. In addition to the evaluation of sensory thresholds (i.e., the detection threshold for
innocuous stimuli and pain threshold), QST includes the assessment of sensations evoked by
30-32suprathreshold stimuli. The German Research Network on Neuropathic Pain (DFNS) developed a&
comprehensive QST protocol consisting of 7 tests measuring 13 parameters and de ned a set of
normative data for thermal and mechanical detection and pain thresholds for the hand, foot, and face
33in healthy volunteers.
The expected role of QST in the de nition of a mechanisms-based approach to NP has not yet been
met. QST has helped to determine selective roles for di" erent peripheral bers or ascending pathways in
34-36speci c conditions. However, there are probably no simple relationships between the pattern of
37sensory de cits and NP symptoms ; and the ultimate aim of marrying clinical symptoms and signs
29with pain pathophysiology still has to be accomplished.
38Max stated that small academic clinical trials so far have failed to identify obvious di" erences in
the response to various drugs of di" erent pain symptoms in the same condition. In contrast, there are
clear di" erences in the analgesic responses of patient groups distinguished on the basis of etiology or
38tissue origin of pain, factors that tend to be associated with groups of mechanisms.
An emphasis has been on supplementing a disease-based treatment approach with one based on
39symptoms (used as an indicator) and their underlying putative mechanisms. This approach accounts
for the observation that patients with one disease entity (e.g., diabetic neuropathy) may have vastly
di" erent symptoms arising from di" erent mechanisms and that patients with di" erent diseases may
40have similar symptoms arising from the same mechanism.
Treatment of NP should be supplemented by the signs and symptoms manifested by the patient as
well as by any pertinent ancillary data including history and physical examination information
challenge testing, imaging electrodiagnostic studies, QST, and skin biopsies. By speci cally targeting the
41mechanisms underlying these symptoms, an improved therapeutic response may be realized. The
clinician may need to explore “rational polypharmacotherapy” on a case-by-case basis when a single
41agent is ineffective in relieving a patient’s reported symptoms.
The challenge for NP diagnosis and assessment is the complexity not only of the primary manifestation
of symptoms but also the many other manifestations of NP as a disease that crosses more than one
domain. For this complexity to be captured and communicated, a model of Multidimensional Pain
42Assessment (MDPA) has been proposed by Backonja and Argoff.
The clinical implications of NP and challenges for the diagnosis and assessment originate from the
fact that the inciting illness or injury may have many consequences in addition to pain. As discussed
previously, each illness, be it PHN or diabetes mellitus, has a speci c clinical course and associated
comorbidities. Those comorbidities may be medical, such as hypertension and hypothyroidism, or
psychiatric, such as depression and anxiety. Medical and psychiatric comorbidities may or may not
further a" ect NP. Even though many comorbidities do not have direct e" ects on the clinical
manifestations of NP, some comorbidities may indirectly a" ect it (e.g., as hypothyroidism, which if
untreated, can contribute to worsening of neuropathy and consequently pain).
Psychiatric comorbidities and pain, in general, may pose an even bigger challenge. In this regard, NP
is perhaps most complicated because of its severity, chronicity, and lack of response to traditional
43treatments. Ploghaus and coworkers, through advances in neuroimaging, elegantly demonstrated a
neural basis for the relationship between anxiety and pain in humans. The in: uence of pain on
psychiatric comorbidities and vice versa are extremely complex and far from clear. The availability of
many speci c assessment tools for human as well as bench research provides ample opportunities to
study those relationships.
42Backonja and Argo" proposed a framework to assist in obtaining a complete clinical picture about
each individual patient. The suggested multidimensional assessment approach (Table 6–3) provides the&
means of assessing critical dimensions of chronic pain speci cally and, on the basis of that assessment,
42rank-ordering components that contribute to the patient’s presentation at any given time. It provides
for the complexity as well as the dynamic nature of pain. Certainly, use of validated pain-intensity
rating scales are still considered the “gold standards” for pain-intensity assessment, but use of a more
comprehensive approach may provide insight into how any particular component of pain, including
multiple components of NP, behave in time and respond to treatments.
Table 6–3 The Multiple Dimensions of Neuropathic Pain
I. Medical etiology related to pain (e.g., diabetes) and medical comorbidities that could influence
manifestation of pain symptoms (e.g., hypothyroidism).
II. Pain mechanisms, such as neuropathic, inflammatory, myofascial.
III. Psychiatric comorbidity (e.g., depression, anxiety), patients’ coping skills, and tendency to
IV. Impact of pain on ability to function (with loss of function comes the disabilities) and quality of life.
The most signi cant implication of applying this approach is the ability to comprehensively assess
pain and to prioritize necessary steps of treatment. Assessment should be made for each dimension and
each dimension should be rated as “none,” “mild,” “moderate,” or “severe” to allow ranking. The
severity of items for each particular dimension would determine the order of further diagnostic
investigations and treatment steps. Clinical experience points to the fact that most, if not all, patients
with chronic painful disorders have diagnoses on each of these dimensions. It is tempting to concentrate
on one component with which the clinician is most comfortable and to ignore others or to see all of the
components as separate and isolated entities. However, it is crucial to remember that these components
interact constantly and have to be considered together.
SAFE (measuring social functioning, analgesia or pain relief, physical functioning, and emotional
functioning) is another multidimensional tool (not speci c to NP) that can be used to assess various
44domains of functioning in patients with persistent pain. Similarly, other investigators have addressed
the need for a multidimensional assessment of persistent pain not only at baseline but also during&
follow-up in efforts to interpret treatment outcomes.
A consensus meeting of the Initiative on Methods, Measurement, and Pain Assessment in Clinical
Trials (IMMPACT) provided recommendations for interpreting clinical importance of treatment
outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments.
A group of 40 participants from universities, governmental agencies, a patient self-help organization,
and the pharmaceutical industry considered methodologic issues and research results relevant to
determining the clinical importance of changes in the speci c outcome measures recommended
assessing four core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical
rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and BPI
interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Pro le of
Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global
45Impression of Change scale (all four domains being assessed by two or more di" erent methods)
(Table 6–4).
Table 6–4 Provisional Clinical Trial Outcome Measures
Finally, although this chapter does not address treatment strategies, a stepwise pharmacologic
management algorithm in the approach to NP is included in order to illustrate current conventional
strategies (Box 6–2).
Reproduced from Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic
pain: evidence-based recommendations. Pain 2007;132:237–251.
Step 1
53,54Assess pain and establish the diagnosis of NP ; if uncertain about the diagnosis, refer to a pain
specialist or neurologist.Establish and treat the cause of NP; if uncertain about availability of treatments addressing NP
etiology, refer to appropriate specialist.
Identify relevant comorbidities (e.g., cardiac, renal, or hepatic disease, depression, gait instability)
that might be relieved or exacerbated by NP treatment or that might require dosage adjustment or
additional monitoring of therapy.
Explain the diagnosis and treatment plan to the patient and establish realistic expectations.
Step 2
Initiate therapy of the disease causing NP, if applicable.
Initiate symptom treatment with one or more of the following:
• A second aryamine TCA (nortriptyline, desipramine) or an SSNRI (duloxetine, venlafaxine).
• A calcium channel α δ ligand, either gabapentin or pregabalin.2
• For patients with localized peripheral NP: topical lidocaine used alone or in combination with one
of the other first-line therapies.
• For patients with acute NP, neuropathic cancer pain, or episodic exacerbations of severe pain, and
when prompt pain relief during titration of a first-line medication to an efficacious dosage is
required, opioid analgesics or tramadol may be used alone or in combination with one of the
firstline therapies.
Evaluate patient for nonpharmacologic treatments, and initiate if appropriate.
Step 3
Reassess pain and health-related quality of life frequently.
If substantial pain relief (e.g., average pain reduced to ≤ 3/10) and tolerable side effects, continue
If partial pain relief (e.g., average pain remains ≥ 4/10) after an adequate trial, add one of the other
first-line medications.
If no or inadequate pain relief (e.g., <_3025_ _reduction29_="" at="" target="" dosage="" after=""
an="" adequate="" _trial2c_="" switch="" to="" alternative="" first-line="">
Step 4
If trials of first-line medications alone and in combination fail, consider second- and third-line
medications or referral to a pain specialist or multidisciplinary pain center.
NP, neuropathic pain; SSNRI, selective serotonin and norepinephrine reuptake inhibitor; TCA,
tricyclic antidepressant.
However, even adhering to these strategies, existing pharmacologic treatments for NP are limited,
45with no more than 40% to 60% of patients obtaining partial relief of their pain.
Thus, many patients may periodically su" er in silence, adjust coping strategies, become a recluse,
55retreat or rest, and/or resort to alternative pain-relieving e" orts. Closs and associates interviewed
patients with persistent pain in attempts to learn about how individual su" erers manage the e" ects of
NP. The most common management strategy was the use of conventional medications, often associated
with poor e" ectiveness and unpleasant side e" ects. Complementary and alternative medicine strategies
were often sought but were largely associated with suboptimal results. Many patients found resting or
55retreating helpful. Patients exhibited a repeating cycle of attempt followed by new attempts. Some&

had tried to accept their pain, but there was insu cient psychological, social, emotional, and practical
55support to allow them to do this successfully.
Currently, optimal therapeutic approaches to NP involve interdisciplinary treatment teams working
closely together with the appropriate use of behavioral medicine, physical medicine, interventional, and
neuromodulation techniques in conjunction with pharmacologic regimes. Future treatment options may
involve agents speci c for modulation of cytokine receptors, TRPV1 receptors, endothelin receptors, as
well as other nociceptive targets.
In summary, advances in pain research, including basic science and clinical research, have provided
ample reason for enthusiasm that progress could be made in the assessment and measurement of pain,
leading to improved pain taxonomy and communication. Consequently, this may potentially lead to the
development of mechanism-based assessment tools and therapies. At present, a number of conceptual,
pathophysiologic, and clinical challenges hamper the diagnosis and treatment of NP.
5However, even though the proposed de nition and grading system of Treede and associates may
serve e" ectively to exclude many cases that are neuropathic in nature to some extent, it does have the
practical and precise nature of being able to correctly identify NP in a more uniform, reproducible, and
concrete manner than just relying on medical judgment after traditional clinician assessments. The
5proposed de nition and grading system of Treede and associates may have a lower sensitivity but a
higher sensitivity than clinician judgment for the identification of NP.
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* A region corresponding to a peripheral innervation territory or to the topographic representation of a
body part in the CNS.
† The suspected lesion or disease is reported to be associated with pain, including a temporal
relationship typical for the condition.
‡ As part of the neurologic examination, these tests con rmed the presence of negative or positive
neurologic signs concordant with the supplemented by laboratory and objective tests to uncover
subclinical abnormalities.
§ As part of the neurologic examination, these tests con rm the diagnosis of the suspected lesion or
5disease. These confirmatory tests depend on which lesion or disease is causing NP.

Chapter 7
Daniel Ciampi de Andrade, Xavier Moisset, Didier
Brain functional imaging has opened up new possibilities for investigating the brain
structures involved in pain perception in humans, providing the elds of neurology
and neuroscience with fruitful insights into the physiology and pathophysiology of
this process.
We review here studies investigating changes in brain activity associated with
experimental and clinical pain by hemodynamic imaging methods:
positronemission tomography (PET) and functional magnetic resonance imaging (fMRI).
Studies using modern electrophysiologic methods (e.g., electroencephalography,
recordings of evoked potentials, magnetoencephalography) are not included here,
although these methods also involve brain imaging. Studies relating to chronic pain
conditions of uncertain origin, such as bromyalgia, irritable bowel syndrome, and
burning mouth syndrome, are also not included.
PET is a nuclear medicine technique for the three-dimensional detection of an
emitting isotope in a certain region of the body. Emitting isotopes are produced in a
cyclotron and are chemically incorporated into a chosen probe molecule. The
choice of the probe molecule depends on the physiologic aspect studied (e.g.,
glucose, water, neurotransmitter receptor agonist). The combination of this
15 18molecule with isotopes to form a complex (H O, F-deoxyglucose) should not2
change the physiologic characteristics of the molecule. As the complex is carried by
the blood stream and arrives at its functional target, the isotope continuously emits
positrons (positively charged electrons). These positrons eventually collide with
electrons within the body. Such collisions release two photons, moving in opposite
directions. These emitted photons are detected by a technique called coincidence
detection, in which two scintillation detectors 180° apart are stimulated

simultaneously. This makes it possible to localize and to quantify the probe
molecule within a selected brain region and is the basis of dynamic detection and
three-dimensional localization in PET studies. However, the scanner detects the site
of the collision, which is not identical to the site at which the positron left the
isotope. Positrons may travel some millimeters within the body before colliding
1with an electron, rendering the spatial resolution of PET scans low (4 mm).
15O is a commonly used isotope in studies of pain. It is combined into natural
15molecules, such as water, to form H O. It is used to detect changes in regional2
2,3cerebral blood 6ow (rCBF) as an indicator of neuronal activity. The results,
expressed as the area “activated,” correspond to the net change in blood 6ow in
this speci c brain region. For the calculation of this net change, it is necessary to
compare the pattern of activation found in the condition studied with a second set
of scans in “control” conditions (e.g., provoked pain vs. rest).
One of the drawbacks of this technique is its poor time resolution, because long
scan periods, of up to 60 seconds, are required. All the hemodynamic changes
occurring during the acquisition period are, therefore, pooled together in the nal
image. Furthermore, only a limited number of scans can be taken, owing to the use
of radioactive molecules, and it may be necessary to study the various conditions of
1interest in different sessions.
One of the advantages of PET is that it can be used to assess physiologic
processes, such as mapping of neurotransmitter systems and drug uptake in vivo,
18depending on the probe molecule chosen. Studies with [ F] 6uorodopa and opioid
receptor ligands have made a major contribution to studies in the eld of pain and
fMRI can be used to detect variations in regional tissue oxygenation due to changes
in oxygen uptake and blood supply to various areas of the brain. Most fMRI studies
are based on a technique in which deoxygenated blood is used as a contrast agent:
blood oxygenation level–dependent (BOLD) imaging. Individuals are usually
scanned in the two sets of conditions to be compared. A voxel-by-voxel substraction
of images from both sets of scans is then undertaken, looking for areas in which
rCBF signi cantly changes across conditions. Deoxyhemoglobin (DeoxyHb)
molecules have four unpaired electrons with paramagnetic properties, modifying
the signal in T -weighted images. A local increase in the ratio of oxy- to2
deoxyhemoglobin results in regional enhancement of the T2-weighted signal,
indicating a net increase in local blood 6ow. This increase is generally linked to a
primary increase in regional metabolism, which may serve as a marker of tissue
synaptic activity and function. Neuronal function is thus indirectly inferred from

hemodynamic measures.
fMRI oCers temporal resolution of 100 msec to 3 seconds, which shortens the
period of painful stimulation during experimental studies, compared with PET
studies. It has a spatial resolution of about 2 mm, allowing a ner anatomic
localization of changes in signal. Because no radioactivity is used, scans may be
repeated an unlimited number of times in a given individual. The drawbacks of this
technique include the presence of pulsation artifacts and the need for strict timing
1of stimulus induction and image acquisition.
fMRI usually gives more false-negative than false-positive results. Because results
depend on a complex statistical analysis of two conditions, a lack of increase in
signal does not necessarily mean that there was no activation in a given area. It
simply means that the increase in signal was not statistically superior to the signal
already present during the control condition.
Hemodynamic studies based on both BOLD fMRI, and PET scans show changes
in rCBF that are generally interpreted as linked to local metabolic changes.
However, it remains unclear whether there is a similar relationship between
hemodynamic and metabolic changes for chronic pain. Both techniques evaluate
local metabolism indirectly, but it is not possible to diCerentiate excitatory from
inhibitory activity. Thus, in a given experiment, a region of the brain may show an
increase in rCBF, but it is not certain whether this region is working to stimulate or
to inhibit the structures connected to it.
Many studies on the use of fMRI and PET to investigate the brain correlates of
experimental pain in normal subjects have been published. Many designs and
experimental paradigms have been used, and certain ndings have been reported
consistently in all studies. Activation in response to experimental painful stimuli
has continuously been reported in a network of brain structures frequently referred
to as the physiologic pain matrix. Six main areas are usually included in the pain
matrix: the primary and secondary somatosensory cortices (S1 and S2), the insular
cortex (IC), the anterior cingulate cortex (ACC), the thalamus (Th), and the
1,4-10prefrontal cortex (PFC) (Fig. 7–1).

Figure 7–1 The physiologic pain matrix. The main regions displaying an
increase in regional cerebral blood 6ow (rCBF) or blood oxygenation level–
dependent (BOLD) responses are indicated. ACC, anterior cingulate cortex; Amy,
amygdala; Cer, cerebellum; DLPF, dorsolateral prefrontal cortex; Ins, insula; OFC,
orbitofrontal cortex; S1, primary somatosensory cortex; S2, secondary
somatosensory cortex; SMA, supplementary motor cortex; Th, thalamus. The
number of stars *, **, *** associated with each structure is a symbolic correlate of
the number of studies showing significant changes.
Adapted from references 1, 4–9.
Pain perception is not identical to nociception. Nociception involves the
physiologic activation of specialized receptors (nociceptors) by noxious stimuli
(e.g., heat, cold, chemical damage, intense pressure). Pain is a much broader
subjective experience, with at least three main aspects or dimensions, and is not
necessarily associated with nociceptor activation. The sensory-discriminative
dimension is related to the quality of the stimulus (e.g., burning, freezing,
pressure), its intensity, location, and temporal pattern. The emotional-aCective
dimension relates to the unpleasantness of pain and its emotional impact, including
autonomic changes. The cognitive-motivational component is related to attention,
memory, and behavioral aspects accompanying the experience of pain. Consistent
with this multidimensional concept of pain, it has been suggested that diCerent
structures from the physiologic pain matrix are preferentially associated with
speci c pain components. Hence, S1, S2, and IC (mostly its posterior portion) are
believed to be preferentially associated with the sensory-discriminative component
of pain. The anterior IC and ACC are believed to be more speci cally linked to the
emotional-aCective aspect of pain. These structures are also involved in empathy
with pain in others. ACC activation, which is frequently reported in pain studies,
may actually be more closely correlated with pain intensity than with stimulus
strength, highlighting the role of this structure in pain evaluation. The PFC, a major
integration center, is also frequently activated during experimental pain and is
related to the cognitive-motivational aspect of pain.
The structures included in the physiologic pain matrix can be schematically

organized into two distinct functional pathways: the medial and the lateral pain
systems. In the lateral pain system, painful signals are conveyed through the
spinothalamic tract (STT) to the ventrolateral nuclei of the thalamus and then to
S1, S2, the parietal operculum, and IC. This lateral system seems to be more
speci cally involved in the sensory-discriminative aspect of pain. In the medial
pain system, pain signals are transmitted through the STT to the medial thalamic
and intralaminar nuclei, and then relayed to the ACC, IC, amygdala, hippocampus,
and hypothalamus. Within this system, information is also transmitted from the
spinal cord to higher centers by other tracts. (e.g., the spinoreticular,
spinomesencephalic, and spinohypothalamic tracts). Thus, the medial system seems
to be more closely related to the cognitive-motivational and emotional-aCective
aspects of pain, including the autonomic and neuroendocrine responses associated
with pain perception.
Brain regions not usually included in the physiologic pain matrix have also been
shown to be activated in several studies of experimental pain. These structures
include the motor/premotor cortex, the supplementary motor area, the
inferior/posterior parietal cortex, the basal ganglia, the cerebellum, and many
brainstem nuclei, particularly the periaqueductal gray matter. The activation of
these areas is often regarded as related to attentional processes and the
preparation, selection, and inhibition of motor responses associated with the
painful stimulus. However, many of these structures have extramotor functions. For
example, the cerebellum receives information indirectly from diCerent association
cortices via the pontine nuclei and passes information on to the motor and
premotor cortices. It is also involved in learning, being activated during verbal
tasks and deactivated after practice. The ventral striata (accumbens and olfactory
tuberculus) have a role in the limbic loop of the basal ganglia circuitry and are
highly connected to the insula, amygdala, and hippocampus. Further studies are
required to determine the speci c role of the activation of these areas in the
presence of pain stimuli.
Hemodynamic brain imaging has been used far less frequently in studies of clinical
pain than in studies of experimental pain. This is probably due to the complexity
and heterogeneity of clinical situations. It is diH cult, for example, to nd suH cient
numbers of homogeneous patients with the same disorder. Many clinical variables
may bias the interpretation of imaging studies. These variables include the duration
and severity of the disease, the presence and type of treatment, and associated
conditions that may change brain activation (e.g., depression, anxiety).
This review is focused on the available information relating to neuropathic pain
and its associated phenomena (e.g., hyperalgesia, allodynia) because this is the

most frequently documented clinical pain type. These ndings are compared with
those obtained in nociceptive pain and complex regional pain syndrome (CRPS)
studies, although data are scarce for these types of pain.
Neuropathic pain is de ned as pain initiated or caused by a primary lesion or
dysfunction in the nervous system. It comprises an enormous group of
heterogeneous conditions, which may be peripheral or central in origin. Its clinical
diagnosis is based on the presence of certain signs and symptoms, the topologic
distribution of which may depend on the site of neural damage. Commonly found
signs include the presence of evoked pain, such as allodynia and hyperalgesia (Fig.
7–2). Allodynia is pain elicited by a normally nonpainful stimulus (e.g., stroking
the skin with a cotton swab). Hyperalgesia corresponds to an increase in the level
of pain caused by a suprathreshold stimulus (e.g., the subject rates his or her pain
higher than would be expected for a given painful stimulation). Evoked pain is
usually associated with spontaneous pain, which may be continuous or paroxysmal,
11-13frequently described as “burning,” “freezing,” or “electric shock–like.”
Figure 7–2 Multiple symptoms in patients with neuropathic pain. The patients
may present various combinations of spontaneous and evoked pain, depending on
diCerent mechanisms. Evoked pain includes both allodynia and hyperalgesia
induced by various types of mechanical and thermal stimuli.
Adapted from Moisset X, Bouhassira D. Brain imaging in neuropathic pain. Neuroimage
2007;37(Suppl 1):S80–88.
The mechanisms of neuropathic pain are poorly understood. However, there is
growing evidence that the diCerent neuropathic symptoms may involve diCerent
mechanisms, and consequently, they may respond diCerently to commonly used
therapeutic molecules. This nding highlights the need to tailor individual
14-17treatment regimens to the symptoms of each patient. Modern brain imaging
has greatly contributed to our understanding of the particular mechanisms of the
many different symptoms present in neuropathic pain.
Imaging Spontaneous Pain in Patients with Neuropathic Pain
Spontaneous pain is a major complaint in patients with neuropathic pain and is a
major cause of disability. It may be continuous or paroxysmal in nature and is
often described as “burning,” “stabbing,” or “tingling.”
Only a few studies and case reports have described changes in brain activity
18during spontaneous neuropathic pain. In 1988, Laterre and coworkers used PET
to evaluate changes in rCBF in a patient with postischemic pain syndrome and
continuous pain (Fig. 7–3A). They described lower levels of glucose utilization in
the contralateral thalamus. This nding has since been reproduced in almost all
19-21studies of spontaneous neuropathic pain. However, the patients included in
these studies were highly heterogeneous. In some studies, it was not entirely clear
20whether the patients suCered true neuropathic pain. In others, the presence of
18continuous, spontaneous pain during the scan was not fully assessed. However,
despite these limitations, these data suggest that the lateral pain system—
particularly S1, S2, and the posterior insula, all of which are major components of
the pain matrix—may not play a major role in spontaneous neuropathic pain. The
underactivation of the contralateral thalamus has been reported, and this result
con6icts with data for microelectrode recordings from the thalamus of patients
22,23with chronic pain undergoing stereotaxic surgery or from animal studies.
Marked hyperactivity has been observed in the thalamic neurons in both of these
situations. It has been suggested that underactivation of the thalamus may result
from deaCerentation due to chronic neuropathic lesions, but this cannot account
for the surprising increase in thalamic signal after analgesic procedures, such as
18cordotomy. A dissociation of blood flow and metabolism has also been suggested,
together with the existence of a possible compensatory mechanism preventing
excessive nociceptive inputs from reaching higher centers. All these possibilities
require further assessment in studies including larger numbers of patients.Figure 7–3 A, Changes in brain activity associated with spontaneous neuropathic
pain. The regions display increases or decreases in rCBF or BOLD responses. B,
Changes in brain activity associated with mechanical allodynia in patients with
neuropathic pain. The regions displaying an increase in activity are indicated in
red. ACC, anterior cingulate cortex; Cer, cerebellum; DLPF, dorsolateral prefrontal
cortex; Ins, insula; LN, lentiform nucleus; OFC, orbitofrontal cortex; PPC, posterior
parietal cortex; S1, primary somatosensory cortex; S2, secondary somatosensory
cortex; SMA, supplementary motor cortex; Th, thalamus; vStr, ventral striatum. The
number of stars *, **, *** associated with each structure is a symbolic correlate of
the number of studies showing significant changes.
A, Adapted from references 18–20, 50; B, adapted from references 24–31.
Imaging Evoked Pain in Patients with Neuropathic Pain
Most studies have focused on dynamic mechanical allodynia (i.e., pain evoked by a
light tactile stimulus, such as a brush stroke). Few studies have analyzed cold
allodynia. Brain activation during the painful stimulus is often compared with the
pattern seen in control scans (during rest or stimulation of the homologous
nonpainful side). These studies have included only small numbers of patients with
diCerent etiologies of pain. Despite these limitations, a fairly consistent response
pattern has been reported for mechanical allodynia. The increase in signal in the
main components of the lateral pain system (S1, S2, and lateral thalamus) was
present in most studies when compared with both nonpainful stimulation of the
24-30homologous contralateral side and rest conditions (see Fig. 7-3B). In contrast,
25,29,31most studies have reported an absence of activation of the ACC and IC.
These ndings may be due to these regions playing no major role in mechanical
allodynia. However, this apparent lack of activation of the ACC and IC may also
have been due to most patients presenting continuous pain in resting conditions.
Thus, these structures were probably already activated during the “painful rest”
condition and were not further activated during allodynic stimulation. Another
region consistently activated in these studies is the PFC. Hemodynamic changes in
the various parts of the PFC (orbitofrontal, medial, and dorsolateral) have been
reported in almost all studies of mechanical allodynia. A recent meta-analysis
showed PFC to be the brain region most frequently activated in studies of chronic
4pain. This structure may be involved not only in the cognitive-evaluative aspect of
pain but also in pain modulation, through its connection with the diencephalon
32and brainstem, as highlighted by the role of this structure in the placebo effect.
Similar results have been reported in studies based on an experimental model of
mechanical allodynia induced by intradermal or topical applications of capsaicin
33-36in normal individuals. In particular, despite the obvious diCerences between
clinical and experimental allodynia, these studies also reported preferential
activation of different sectors of the various regions of the PFC.
Thus, mechanical allodynia does not seem to involve the whole physiologic pain
matrix but, rather, a preferential activation of the sensory-discriminative lateral
pain system and the PFC. The sharp contrast between this pattern of activation and
that associated with spontaneous pain is consistent with the involvement of
different mechanisms in specific components of neuropathic pain syndromes.
Very few studies have assessed the changes in brain activity associated with cold
27-29allodynia. The only direct comparison of brain activation associated with cold
and dynamic allodynia in a small group of patients with syringomyelia suggested
29that these two subtypes of allodynia induced distinct changes in brain activity.
However, further studies with a larger number of patients are required to
determine whether this diCerence re6ects true diCerences in the mechanisms of
these two types of allodynia.
CRPS I (formerly known as sympathetic re6ex dystrophy) is characterized by
disproportionate pain (both spontaneous and evoked) associated with local
autonomic and trophic disturbances occurring after minor trauma in the absence of
a detectable nerve lesion. The pathophysiology of this syndrome is unclear. CRPS I
and neuropathic pain display similarities in clinical presentation, resulting in
suggestions that they may involve common mechanisms. Studies assessing
mechanical allodynia (both dynamic and static) in CRPS I patients have generally

compared the pattern of brain activation on the painful side with that on the
homologous contralateral (nonpainful) side. They have reported activation of the
37-39lateral (S1, S2) and medial (insula, ACC, PFC) pain systems. The presence of
ACC activation reported in most studies contrasts with the ndings obtained for
mechanical allodynia associated with well-de ned neuropathic pain. This
highlights the diH culty involved in identifying the role in pain perception of a
complex structure, such as the ACC, which may be more active in pain anticipation
and evaluation than in pain perception itself. There is also a growing body of data
to suggest that the diCerent regions of the ACC have diCerent functions in the
integration of homeostatic information provided by the limbic cortex and the
cognitive-evaluative processes taking place in the PFC. Also, the more posterior part
of the ACC has been shown to be positively related to the intensity of the induced
37allodynic pain in CRPS I patients. This region is closer to the motor cortex and
would allow for faster motor responses to diverge from painful stimuli. The more
anterior ACC, which is closer to heteromodal association cortices, would be
involved in the cognitive evaluation of a painful stimulus. However, it remains
unclear whether this relationship between the diCerent ACC regions and their
respective functions is also present in other chronic pain syndromes.
CRPS I is associated with dynamic changes in brain activity, as suggested by a
study comparing the brain activity evoked by heat stimuli before and after a
40sympathetic block (SB). In the subgroup of patients who responded to the SB, it
was found that an overactivation of PFC and ACC and an underactivation of the
contralateral thalamus were all reversed after successful pain control by the
Cortical reorganization, which is characterized by a reduction in the BOLD signal
in S1 and S2 during nonpainful tactile stimulation of the aCected limb, has also
been reported in CRPS I patients. The pain relief associated with behavioral
therapy over 1 to 6 months was correlated with the restoration of tactile
discrimination task scores and an increase in S1/S2 signals contralateral to the
41affected limb.
Very few imaging studies have been carried out on patients with chronic
nociceptive pain. Most of these studies did not assess clinical pain directly. Instead,
they investigated responses to experimental pain (painful heat or pressure) in
patients with chronic nociceptive pain (Fig. 7-4).
Figure 7–4 Changes in brain activity associated with experimentally evoked
pain in low back pain (LBP) and rheumatoid arthritis patients. The regions
displaying an increase in rCBF or BOLD responses are indicated. ACC, anterior
cingulate cortex; Cer, cerebellum; DLPF, dorsolateral prefrontal cortex; Ins, insula;
LN, lentiform nucleus; OFC, orbitofrontal cortex; S1, primary somatosensory cortex;
S2, secondary somatosensory cortex; Th, thalamus. The number of stars *, **, ***
associated with each structure is a symbolic correlate of the number of studies
showing significant changes.
Adapted from references 44, 46–49.
In a study in patients with rheumatoid arthritis (RA), a classic model of chronic
nociceptive pain, painful heat stimuli induced a decrease in rCBF in the PFC and
ACC. ECective coping strategies in these patients have been proposed to explain
42,43these surprising observations. However, con6icting results were reported in a
44more recent study from the same group assessing the patterns of brain activation
in RA patients at rest, during acute spontaneous arthritis-related pain, and
experimental heat pain. In this study, the authors reported a stronger signal in
structures from the medial pain system (ACC, amygdala, and orbitofrontal cortex
[OFC]) for arthritic pain than for evoked pain. The unpleasantness of pain was also
closely correlated with the activation of these structures, but no major
hypoactivation was described. These apparently con6icting results may be
43accounted for by the small number of patients (six) evaluated in the first study.
Low back pain (LBP) is a highly prevalent condition and is the second most
45frequent symptom-related reason for which patients consult a physician. It is
frequently classi ed as a type of nociceptive pain, although its mechanisms are
probably complex and remain poorly understood. It may be idiopathic or
secondary to various conditions (e.g., fractures, inflammatory diseases, surgery).
An elegant study showed a diCerential pattern of activation during two diCerent
components of spontaneous pain in LBP patients: “increasing” and “high constant"
46pain. During an increase in spontaneous pain, an increase in the signal from the
IC, S1, S2, mid-ACC, and cerebellum was detected. Changes in IC activity were

found to be positively correlated with the increase in spontaneous pain. In contrast,
when pain remained at high constant levels, the activity of the medial PFC
(including the rostral ACC) increased; this increase being directly correlated with
pain intensity. Interestingly, these authors also described a decrease in cortical
47density in the same area of the dorsolateral PFC (DLPF) in LBP patients.
In LBP patients, the application of a painful heat stimulus to the lower back
induced a signi cantly stronger bilateral signal in the IC, S2, and ACC and a
signi cantly stronger signal in the right DLPF than that observed in normal
Other studies have evaluated brain processing in LBP patients during
48experimental pain distant from the lower back region. Derbyshire and colleagues
compared responses to painful heat stimulation of the hand in LBP patients.
Activation, mostly observed in the cerebellum, midbrain, thalamus, lentiform
nucleus, PFC, midcingulate cortex, and IC, was similar in patients and controls. In
another study, painful pressure stimuli applied to the thumb induced similar
patterns of brain activation in patients with LBP (or bromyalgia) and controls, but
49the intensity of the signals was greater in patients.
These studies in patients with RA and LBP tend to con rm that the changes in
brain activity associated with clinical nociceptive pain are diCerent, at least
quantitatively, from those induced by experimental pain. In particular, chronic
clinical nociceptive/in6ammatory pain seems to be more speci cally associated
with changes in the medial pain system.
Modern functional imaging of the brain has helped to improve our understanding
of the mechanisms of normal physiologic pain and, to a much lesser extent, of some
speci c clinical pain states. The available data tend to indicate that pathologic
pain does not correspond simply to the abnormal activation of a single "pain
matrix," but rather that diCerent types of pain (e.g., neuropathic, nociceptive) and
probably diCerent pain symptoms (spontaneous continuous pain, allodynia)
involve diCerent brain mechanisms. These ndings highlight the need for a more
rational and pathophysiologic classi cation of pain syndromes. Future studies
should also help to de ne the place of functional neuroimaging in
mechanismbased approaches to chronic pain.
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Chapter 8
Howard S. Smith, Kenneth L. Kirsh
The eld of pain management is still relatively young compared with other medical specialties, but it has
experienced a tremendous period of growth since the late 1980s. Realization has grown that chronic pain
a ects the lives of millions of people and that this issue must be addressed. Indeed, we see that issues with
pain are the number-one reason that patients go to see their physicians. However, this increased recognition
of the problem has been somewhat tempered by the souring of the regulatory climate and the growth of
prescription drug abuse. Because of this, there has been a trend for clinicians to shy away from using high
opioid doses or even utilizing this modality at all in the treatment of chronic pain (Box 8–1).
• Problems with prescription drug abuse and diversion have created a heightened level of tension and fear
over the use of opioids in pain management.
• It is essential that pain clinicians provide a rationale for engaging in this modality of treatment and
provide ample documentation in this regard.
• Assessment and documentation are cornerstones for both protecting your practice and obtaining optimal
patient outcomes while on opioid therapy.
Despite these fears and concerns, the use of long-term opioid therapy (OT) to treat chronic nonmalignant
pain is growing, based in part on evidence from clinical trials and a growing consensus among pain
specialists. The appropriate use of these drugs requires skills in opioid prescribing, knowledge of addiction
medicine principles, and a commitment to perform and document a comprehensive assessment repeatedly
over time. Inadequate assessment can lead to undertreatment, compromise the e ectiveness of therapy
when implemented, and prevent an appropriate response when problematic drug-related behaviors occur.
There is a burgeoning interest in the development of tools that can be useful for screening patients up
front to determine the relative risk for patients having problems with prescription drug abuse or misuse (Box
8–2). To date, a number of tools have arisen, including the Screening Tool for Addiction Risk (STAR), Drug
Abuse Screening Test (DAST), Screener and Opioid Assessment for Patients with Pain (SOAPP), and the
Opioid Risk Tool (ORT). The choice in tools for a more thorough ongoing assessment, however, has been
somewhat more limited up until now and is the focus of the discussion.
• Several potential tools and documentation strategies are available that will aid clinicians in providing
evidence for the continuation of this type of treatment for their patients.
• The Pain Assessment and Documentation Tool (PADT) is a global charting tool that captures domains of
analgesia, activities of daily living, adverse side effects, and potentially aberrant drug-taking behaviors.
• The Numerical Opioid Side Effect (NOSE) assessment tool is a specific instrument designed for the
quantification of adverse effects.
• The Translational Analgesia Scale (TAS) is a patient-generated tool that attempts to quantify the degree
of “translational analgesia” or improvements in various domains over time as a result of treatment.



Oversight by regulatory agencies, state medical boards, and various peer-review groups includes
examination of appropriate medical care as well as proper documentation. As the old axiom states, “if it
isn’t written, it didn’t happen.” In cases of OT for chronic pain, issues beyond typical o8 ce visit charting
may deserve attention and documentation. Although there are no explicit requirements for what and how to
document issues related to OT, it is belived by some that the use of speci c tools and instruments in the
chart on some or all visits may boost adherence to documentation expectations as well as the consistency of
such documentation. Assessment tools may also be helpful in the analysis of persistent pain.
It is important to consider four main domains in assessing pain outcomes and to better protect your practice
for those patients you maintain on an opioid regimen: (1) pain relief, (2) functional outcomes, (3) side
e ects, and (4) drug-related behaviors. These domains have been labeled the “Four A’s” (Analgesia,
Activities of daily living, Adverse e ects, and Aberrant drug-related behaviors) for teaching purposes. There
are, of course, many di erent ways to think about these domains, and multiple attempts to capture them
are discussed later.
The Pain Assessment and Documentation Tool (PADT) is a simple charting device, based upon the Four A’s,
that is designed to focus on key outcomes and provide a consistent way to document progress in pain
management therapy over time. Twenty-seven clinicians completed the preliminary version of the PADT for
388 opioid-treated patients. The result of this work is a brief, two-sided chart note that can be readily
included in the patient’s medical record. It was designed to be intuitive, pragmatic, and adaptable to
clinical situations. In the eld trial, it took clinicians between 10 and 20 minutes to complete the tool. The
revised PADT is substantially shorter and should require a few minutes to complete. By addressing the need
for documentation, the PADT can assist clinicians in meeting their obligations for ongoing assessment and
documentation. Although the PADT is not intended to replace a progress note, it is well suited to
complement existing documentation with a focused evaluation of outcomes that are clinically relevant and
address the need for evidence of appropriate monitoring.
The decision to assess the four domains subsumed under the shorthand designation the “Four A’s” was
based on clinical experience, the positive comments received by the investigators during educational
programs on opioid pharmacotherapy for nonmalignant pain, and an evolving national movement that
recognizes the need to approach OT with a “balanced” response. This response recognizes both the
legitimate need to provide optimal therapy to appropriate patients and the need to acknowledge the
potential for abuse, diversion, and addiction. The value of assessing pain relief, side e ects, and aspects of
functioning has been emphasized repeatedly in the literature. Documentation of drug-related behaviors is a
relatively new concept being explored for the first time in the PADT.
Documentation of adverse e ects in a majority of charts from many pain clinics tends to be addressed in the
chart by a brief note of the presence or absence of one or more adverse e ects (e.g., nausea, constipation,
itching) recorded by busy clinicians. Similar to the goal of the PADT, having a standardized form that is
used at every visit and lled out by the patients before being seen by health care providers may provide
certain advantages.
Patients with persistent pain on oral OT have asked to “come o ” the opioids because of adverse e ects,
even if they perceived that opioids were providing reasonable analgesic e ects. The distress that may be
caused by opioid adverse e ects may also be seen in acute postoperative pain patients, who may
occasionally ask to stop their opioids (despite the perception that these are e ective analgesics) because of
the signi cant distress and su ering that they believe they are experiencing from an opioid adverse e ect.
Therefore, it appears crucial to assess opioid adverse e ects. Ideally, this should be done in a manner that
allows the clinician to follow trends as well as to compare the patient’s perceived intensity of the adverse


effects versus the intensity of pain and/or other symptoms or adverse effects.
The Numerical Opioid Side E ect (NOSE) assessment tool (Appendix 8–1) is a self-administered survey
that can be completed by the patient in minutes and entered into an electronic database or inserted into a
hard-copy chart on each patient visit. The NOSE assessment tool is easy to administer and to interpret and
may provide clinicians with important clinical information that could potentially a ect various therapeutic
decisions. Although most clinicians probably routinely assess adverse e ects of treatments, it is sometimes
di8 cult to nd legible, clear, and concise documentation of such information in outpatient records.
Furthermore, the documentation that does exist may not always attempt to “quantify” the intensity of
treatment-related adverse effects or lend itself to looking at trends (see Appendix 8–1).
The Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT) recommended
that six core outcome domains—(1) pain, (2) physical functions, (3) emotion, (4) participant rating of
improvement and satisfaction with treatment, (5) symptoms and adverse events, and (6) participant
disposition—should be considered when designing chronic pain clinical trials. The authors believe that the
use of a unidimensional tool such as the numeric rating scale-11 (NRS-11) provides a suboptimal
assessment of chronic pain as well as OT e8 cacy. Clinicians should attempt to assess multiple domains
(preferably with multidimensional tools) in e orts to achieve a global picture of the patient’s baseline status
as well as the patient’s response to OT in various domains.
It has been proposed that the use of a collection of various tools may provide adjunct information and
help clinicians to create a more complete picture regarding longitudinal trends of overall
progress/functioning for their patients with chronic pain on OT. Assessing individual outcomes during
outpatient multidisciplinary chronic pain treatment is often an extremely challenging task. Many tools and
instruments are currently available, but the Treatment Outcomes in Pain Survey tool (TOPS) has been
speci cally designed to assess and follow outcomes in the chronic pain population and has been described
as an augmented SF-36. The Medical Outcomes Study (MOS) Short Form 36-item questionnaire (SF-36)
compares the health status of large populations without a preponderance of one single medical condition.
The SF-36 assesses eight domains, but it has not been found to be especially useful for following the changes
in function and pain in chronic pain populations.
The eight domains of the SF-36 are bodily pain (BP), general health (GH), mental health (MH), physical
functioning (PF), role emotional (RE), social functioning (SF), role physical (RP), and vitality (VT). The
TOPS scale initially had nine domains, but one (satisfaction with outcomes) was modi ed in subsequent
versions. The nine domains of TOPS are Pain Symptom, Family/Social Disability, Functional Limitations,
Total Pain Experience, Objective Work Disability, Life Control, Solicitous Responses, Passive Coping, and
Satisfaction with Outcomes. This enhanced SF-36 (TOPS scale) was constructed by obtaining patient data
from the SF-36 with 12 additional role functioning questions. These additional questions were taken in part
from the 61-item Multidimensional Pain Inventory (MPI) and the 10-item Oswestry Disability
Questionnaire, with four additional pain-related questions similar to those found in the MOS pain-related
questions, the Brief Pain Inventory, and a six-item coping scale from the MOS.
The questions adapted from the Oswestry Disability Questionnaire (designed for back pain patients)
include questions that relate to impairment (pain), physical functioning (how long the patient can sit
and/or stand), and disability (ability to travel or have sexual relations). The patient-generated index is an
instrument that attempts to individualize a patient’s perception of their quality of life.
Although the TOPS instrument is an extremely useful tool, it is time-consuming, is based entirely on the
patient’s subjective responses, and requires that the clinician has access, whether by a special computer
program or by sending forms away, for scoring. As a result, it may not be an ideal instrument to use in
every pain clinic and may not provide the clinician with an immediate answer of how the patient is doing
relative to previous visits (although it may have that potential with adequate time, scanning equipment,
and computer software).


A concept that may possess potential utility for clinicians is translational analgesia. Translational analgesia
refers to improvements in physical, social, or emotional function that are realized by the patient as a result
of improved analgesia, or essentially, what did the pain relief experienced by the patient “translate” into in
terms of perceived improved quality of life. In most cases, a sustained and signi cant improvement in pain
perception that is deemed worthwhile to the patient should “translate” into improvement in quality of life
or improved social, emotional, or physical function. Improvements in social, emotional, or physical domains
are often spontaneously reported by patients but, in most cases, should be able to be ascertained or elicited
via “focused” interview techniques with the patient, signi cant others, and family, “focused” physical
examination, or a combination of any of these. Improvements may be subtle and could include a range of
daily function activities or other signs (e.g., going out more with friends, doing laundry, showing improved
mood/relations with family members). It is important to note that this issue is certainly not exclusive to OT
and is believed to apply to other treatments.
The authors do not deem it inappropriate or inhumane to taper relatively “high-dose” OT in a patient
with chronic pain who notes that her or his NRS-11 pain score has dropped from 9/10 to 8/10 after
escalating to more than 1 g of long-acting morphine preparation per day, but in whom the patient as well as
the patient’s family or signi cant other cannot describe (and the clinician cannot elicit) any signi cant
“translational analgesia.” A patient with chronic pain who demonstrates a failure to “get o the couch,”
despite equivocal or minimally improved analgesia, should not be considered as a therapeutic success. But
should this viewpoint be seen as cruel or as a punishment for these patients? Rome and colleagues
demonstrated that at least a subpopulation of patients seems to do better after tapering o opioids.
Furthermore, more evidence regarding the hyperalgesic actions of opioids in certain circumstances is
The periodic assessment of the patient with chronic pain should be performed in multiple domains (e.g.,
social, analgesia, functional, emotional). The authors believe to be suboptimal the relatively common
practice of evaluating patients with chronic pain by obtaining a NRS-11 pain score at each assessment and
basing opioid analgesic treatment solely on this score. Although tools exist that assess multiple domains used
in research, there is no simple, convenient, and universally acceptable instrument that is utilized in busy
clinical pain practices.
To address this issue, a recent tool has been developed. The SAFE Score is a multidomain assessment tool
that may have potential utility for rapid dynamic assessment in the busy clinic setting. The SAFE Score is a
clinician-generated tool and may be best utilized in conjunction with the Translational Analgesic Score (TAS;
a patient-generated tool) as an adjunct. These are discussed, in turn, in the following sections.
The TAS is a patient-generated tool that attempts to quantify the degree of “translational analgesia”
(Appendix 8–2). It is simple, rapid, user-friendly, and suitable for use in busy pain clinics. The patient can
be handed the TAS sheet with questions to ll out at each visit while in the waiting room and the responses
are averaged for an overall score, which is recorded in the chart. The authors encourage clinicians to have
all patients write down speci c examples of things that they can do now or do frequently that they could
not do or did rarely when their pain was less controlled. Alternatively, the patient’s responses can be entered
into a computerized record (with graphs of trends) if the pain clinic’s medical records are electronic.
In the sample provided, the patient answered all 10 questions with responses; hence, the average is the
sum of all responses (26) divided by 10. Therefore, the TAS is 2.6. A patient who at each visit consistently
has a TAS of 10.0 clearly represents a therapeutic success on her or his current treatment. Conversely, a
patient who at each visit consistently has a TAS of 0.0 would represent a suboptimal therapeutic result (by
TAS criteria). Clinicians are encouraged to document at least one or two speci c examples of translational
analgesia (e.g., perhaps various activities the patient can now perform as a result of pain relief or can now
perform frequently as a result of pain relief that the patient could not do or do only infrequently
pretherapy) on the bottom or reverse side of the TAS sheet. Treatment decisions regarding escalation or
tapering of opioids, changing agents, adding agents, obtaining consultations, instituting physical medicine
or behavioral medicine techniques remain the medical judgment of practitioners and should be based on a"

careful reevaluation of the patient and not on a number.
The concept of translational analgesia is not meant to imply that opioids should be tapered, weaned,
and/or discontinued. If a patient has a very low TAS that and essentially unchanged over time (especially in
conjunction with a SAFE score in the “red zone”), then this should prompt the clinician to reevaluate the
patient and consider a change in therapy. This could mean pursuing various therapeutic options including
perhaps increasing the dose of opioids. However, if a patient has a high TAS and a SAFE score in the green
zone, the patient should probably continue OT.
Another tool advocated to help with this purpose is SAFE Score. Although it has not yet been rigorously
validated, it is simple and practical and may possess clinical utility. It is a score generated by the health
care provider that is meant to reKect a multidimensional assessment of outcome to OT. It is not meant to
replace more elaborate patient-based assessment tools but could possibly serve as an adjunct and possibly in
the future shed some light on the di erence between patients’ perceptions of how they are doing on OT
versus the physician-based view of outcome.
At each visit, the clinician rates the patient’s functioning and pain relief in four domains. The domains
assessed include social functioning (S), analgesia or pain relief (A), physical functioning (F), and emotional
functioning (E). The ratings in each of the four domains are combined to yield a SAFE score, which can
range from 4 to 20.
The SAFE Tool is both practical in its ease and clinically useful (Appendix 8–3). The goals of the SAFE
Tool are multifold. Speci cally, they include the need to demonstrate that the clinician has routinely
evaluated the e8 cacy of the treatment from multiple perspectives; to guide the clinician toward a broader
view of treatment options beyond adjusting the medication regimen; and to document the clinician’s
rationale for continuation, modification, or cessation of OT.
Interpretation of Scores
Scores can be broken down into three distinct categories. First, the green zone represents a SAFE score of 4
to 12 and/or a decrease of 2 points in the total score from baseline. With a score in the green zone, the
patient is considered to be doing well and the plan would be to continue with the current medication
regimen or consider reducing the total dose of the opioids. Second, the yellow zone represents a SAFE score
of 13 to 16 and/or a rating of 5 in any category and/or an increase of 2 or more from baseline in the total
score. With a score in the yellow zone, the patient should be monitored closely and reassessed frequently.
Finally, the red zone represents a SAFE score of 17 or higher. With a score in the red zone, a change in the
treatment would be warranted (Tables 8-1 to 8-3).
Table 8–1 Green Zone Cases Using the SAFE Scoring Tool
Table 8–2 Tracking a Change in Status Using the SAFE Scoring Tool

Table 8–3 Tracking a Specific Domain Change in Status Using the SAFE Scoring Tool
Once the color determination is made, a decision can be made regarding treatment options. Treatment
options depend on the pattern of scores. If attempts are made to address problems in speci c domains and
the patient is still not showing an improvement in the SAFE score, the patient may not be an appropriate
candidate for long-term OT.
Table 8–1 illustrates green zone cases. Example A shows good analgesic response to opioids, with a fair
response in the other domains. No change in treatment would be necessary unless adverse reactions to the
medications require an adjustment or discontinuation. Example B illustrates borderline analgesic response,
but good social and emotional responses and a fair physical functioning response. Some pain specialists may
determine that the medication regimen should be optimized. For others, this pattern of ratings may reKect a
reasonable improvement in quality of life for the patient. Therefore, continuing the present medication
regimen would be a reasonable option.
Table 8–2 illustrates how the SAFE tool can be used to track changes in the status of the same patient on
two consecutive visits. In the change in scores from example C to example D, although analgesia
deteriorates from fair to borderline, signi cant improvement is shown in the other domains. The clinician
may feel this is satisfactory for this particular patient and continue with the current medication regimen.
Once again, too narrow a focus on analgesic response may lead to unnecessary dose escalation. This case
also illustrates the situation in which even though the total score at visit D is greater than 12 and would be a
yellow zone, it is assigned as a green zone because there was a decrease of more than 2 in the total score.
Alternately, the clinician may determine that a borderline analgesic response is not optimal. The choices for
intervention may include rotating to another opioid agent, increasing the current opioid dose, adding
adjuvant medications, referring for nonpharmacologic treatment, or discontinuing high-dose opioids.
Table 8–3 again illustrates a single patient on two consecutive visits. Here, analgesia has remained good
over time, but there has been a negative impact on the domains of function and emotion. Pain specialists
who are focused on the pain scores of such a patient may be comfortable with continuing the established
treatment plan. However, using SAFE, an expanded view of the patient’s overall status will alert the
clinician to monitor the patient’s physical and emotional functioning in future visits. If the ratings in the
psychological and physical domains persist, the clinician may recommend that the patient pursue
psychosocial treatment or physical rehabilitation in addition to maintaining the medication regimen.
Assessment and documentation are cornerstones for both protecting your practice and obtaining optimal"
patient outcomes while on opioid therapy. A growing number of assessment tools exist for clinicians to
guide the evaluation of a group of important outcomes during OT and provide a simple means of
documenting patient care. They all have the capability to prove helpful in clinical management and o er
mechanisms for documenting the types of practice standards that those in the regulatory and law
enforcement communities seek to ensure.
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Friedman R, Li V, Mehrotra D. Treating pain patients at risk: evaluation of a screening tool in opioid-treated
pain patients with and without addiction. Pain Med. 2003;4:182-185.
Katz N. The impact of pain management on quality of life. J Pain Symptom Manage. 2002;24(suppl 1):S38-S47.
Lipman AG. Does the DEA truly seek balance in pain medicine? J Pain Palliat Care Pharmacother. 2005;19:7-9.
McCarberg BH, Barkin RL. Long-acting opioids for chronic pain: pharmacotherapeutic opportunities to enhance
compliance, quality of life, and analgesia. Am J Ther. 2001;8:181-186.
Passik SD, Kirsh KL. Fear and loathing in the pain clinic. Pain Med. 2006;7:363-364.
Passik SD, Kirsh KL, Whitcomb LA, et al. A new tool to assess and document pain outcomes in chronic pain
patients receiving opioid therapy. Clin Ther. 2004;26:552-561.
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For each of the following questions—respond by comparing your current state over the past month to your
baseline status before you started your current treatment regimen by circling a number from 0 to 10, with 0
being no improvement and 10 being maximal improvements:
1. Over the past month, my pain treatment has improved my ability to do usual daily activities—including
household work, work, school, and/or social activities.
2. Over the past month, my pain treatment has improved my ability to concentrate on work or daily
3. Over the past month, my pain treatment has improved the degree to which I feel too tired to do work
(feeling that I could not get going and everything I did was an effort) or too tired to perform daily activities
and/or socialize because of my pain.
4. Over the past month, my pain treatment has improved the degree to which I feel distress, restless,
agitated, or could go and lie down and/or be alone because of my pain.
5. Over the past month, my pain treatment has improved my mood or feelings of being: depressed,
frustrated, anxious, irritable, tense, hopeless, annoyed, or just plain fed up because of my pain.
6. Over the past month, my pain treatment has improved my ability to sleep.
7. Over the past month, my pain treatment has improved my ability to walk, sit, and/or stand for long
8. Over the past month, my pain treatment has improved my ability to go up stairs and/or move or lift
9. Over the past month, my pain treatment has improved the extent to which my pain interferes with
optimal interpersonal relationships and/or intimacy.
10. Over the past month, to what degree have you, your significant other, your family, your coworkers,
and/or your friends noticed any improvements in your socializing, recreational activities, physical
functioning, concentration, mood, interpersonal relationships, activities of daily living, and/or overall
quality of life?
—Please write below—speci c examples of things you can do now or currently do frequently that you
could not do or did only rarely when your pain was not controlled as well as it is now.
TAS = _______________
The TAS is expressed as a number between 0 to 10 with a decimal being the average of the responses to
the 10 questions (or fewer—if the patient is paraplegic, then she or he would not answer the questions
regarding going up stairs, etc.).
As an example, a patient’s response to the TAS tool is shown below:
1. Over the past month, my pain treatment has improved my ability to do usual daily activities— including
household work, work, school, and/or social activities.
2. Over the past month, my pain treatment has improved my ability to concentrate on work or daily
3. Over the past month, my pain treatment has improved the degree to which I feel too tired to do work
(feeling that I could not get going and everything I did was an effort) or too tired to perform daily
activities, and/or socialize because of my pain.
4. Over the past month, my pain treatment has improved the degree to which I feel distress, restless,
agitated, or could go and lie down and/or be alone because of my pain.
5. Over the past month, my pain treatment has improved my mood or feelings of being: depressed,
frustrated, anxious, irritable, tense, hopeless, annoyed, or just plain fed up because of my pain.6. Over the past month, my pain treatment has improved my ability to sleep.
7. Over the past month, my pain treatment has improved my ability to walk, sit, and/or stand for long
8. Over the past month, my pain treatment has improved my ability to go up stairs, and/or move or lift
9. Over the past month, my pain treatment has improved the extent to which my pain interferes with
optimal interpersonal relationships and/or intimacy.
10. Over the past month, to what degree have you, your significant other, your family, your coworkers,
and/or your friends noticed any improvements in your socializing, recreational activities, physical
functioning, concentration, mood, interpersonal relationships, activities of daily living, and/or overall
quality of life?
TAS = 2.6
Appendix 8–3 Sample SAFE FormIII

Chapter 9
Scott S. Reuben
The primary goal of postoperative pain relief is to provide subjective comfort, inhibit
trauma-induced a erent pain transmission, and blunt the autonomic and somatic re ex
responses to pain. By accomplishing this, we should enhance restoration of function by
allowing the patient to breath, cough, and ambulate more easily. Subsequently, these
e ects should improve overall postoperative outcome. Despite our increased knowledge
of the pathophysiology and pharmacology of nociception since the late 1990s, acute
1postoperative pain still remains a major problem. Patients continue to report that their
1,2primary concern before surgery is the severity of postoperative pain. This is justi) ed,
because one survey revealed that 31% of patients su ered from severe or extreme pain
1and another 47% from moderate pain.
Unrelieved postoperative pain may not only result in su ering and discomfort but also
lead to multiple physiologic and psychological consequences, which can contribute to
3adverse perioperative outcomes. This can potentially contribute to a higher incidence of
4,5myocardial ischemia, impaired wound healing, and delayed gastrointestinal motility,
6resulting in prolonged postoperative ileus. Further, unrelieved acute pain leads to poor
respiratory effort and splinting that can result in atelectasis, hypercarbia, and hypoxemia,
3contributing to a higher incidence of postoperative pneumonia. In addition, acute pain
causes psychological distress and anxiety, leading to sleeplessness and helplessness,
impairing postoperative rehabilitation, and potentially causing long-term psychological
7consequences. Finally, it has been recognized that unrelieved acute pain may contribute
8to a higher incidence of chronic postsurgical pain. Therefore, strategies aimed at
reducing acute pain may not only provide subjective comfort for our patients but also
result in improved postoperative outcomes and a reduction in health care expenditures.
Peripheral sensitization, a reduction in the threshold of nociceptor a erent peripheral
9terminals, is a result of in ammation at the site of surgical trauma. Central sensitization,
an activity-dependent increase in the excitability of spinal neurons, is a result of
10persistent exposure to nociceptive a erent input from the peripheral neurons. Taken
together, these two processes contribute to the postoperative hypersensitivity state
(“spinal windup”) that is responsible for a decrease in the pain threshold, both at the site
of injury (primary hyperalgesia) and in the surrounding uninjured tissue (secondary

11hyperalgesia) (Fig. 9–1).
Figure 9–1 Surgical trauma leads to the release of in ammatory mediators at the site of
injury, resulting in a reduction in the pain threshold at the site of injury (primary
hyperalgesia) and in the surrounding uninjured tissue (secondary hyperalgesia).
Peripheral sensitization results from a reduction in the threshold of nociceptor a erent
terminals secondary to surgical trauma. Central sensitization is an activity-dependent
increase in the excitability of spinal neurons (spinal wind-up) as a result of persistent
exposure to a erent input from peripheral neurons. BK, bradykinin; CNS, central nervous
system; 5-HT, serotonin; PGs, prostaglandins.
As a result of this peripheral sensitization, low-intensity stimuli that would normally
not cause a painful response prior to sensitization now become perceived as pain, an
effect termed allodynia (Fig. 9–2).

Figure 9–2 Nociceptive a erent input from trauma can sensitize the nervous system to
subsequent stimuli. The normal pain response as a function of stimulus intensity is
depicted by the curve on the right. After trauma, the pain response curve is shifted to the
left. As a result, noxious stimuli become more painful (hyperalgesia), and nonpainful
stimuli (shaded region) now become painful (allodynia).
The proin ammatory cytokine interleukin-1β (IL-1β) is up-regulated at the site of
in ammation and plays a major role in inducing cyclooxygenase-2 (COX-2) in local
12in ammatory cells by activating the transcription factor nuclear factor B (NF-kB).
IL1β is also responsible for the induction of COX-2 in the central nervous system (CNS) in
response to peripheral in ammation. Interestingly, it is not the consequence either of
neural activity arising from the sensory ) bers innervating the in amed tissue or of
systemic IL-lβ in the plasma. Instead, peripheral in ammation produces some other
signal molecule that enters the circulation, crosses the blood-brain barrier, and acts to
elevate IL-lβ, leading to COX-2 expression in neuronal and nonneuronal cells throughout
13-15the CNS. Thus, there appear to be two forms of input from peripheral in amed
tissue to the CNS. The ) rst is mediated by electrical activity in sensitized nerve ) bers
innervating the in amed area, which signals the location of the in amed tissue as well as
16the onset, duration, and nature of any stimuli applied to this tissue. This input is
sensitive to peripherally acting COX-2 inhibitors and to neural blockade with local
17anesthetics, as with epidural or spinal anesthesia. The second is a humoral signal
originating from the in amed tissue, which acts to produce a widespread induction of
13,14COX-2 in the CNS. This input is not a ected by regional anesthesia and will be
14,17,18blocked only by centrally acting COX-2 inhibitors. One implication of this is that
patients who receive neuraxial anesthesia for surgery might also need a centrally acting
COX-2 inhibitor to optimally reduce postoperative pain and the postoperative stress
14,17,18response. Therefore, the permeability of the blood-brain barrier to currently used
nonsteroidal anti-in ammatory drugs (NSAIDs) and COX-2 inhibitors becomes
In July 2000, the Joint Commission for Accreditation of Health Care Organizations

(JCAHO) introduced a new standard for pain management, declaring pain level to be the
20“) fth vital sign.” The Commission concluded that acute and chronic pain were major
causes of patient dissatisfaction in our health care system, leading to slower recovery
times, creating a burden for patients and their families, and increasing the costs to the
20health care system. However, the increased e orts aimed at reducing patients’
postoperative pain scores may have further increased the risk of adverse e ects when
21-23health care providers attempted to achieve sufficient analgesia by opioids alone.
The concept of multimodal analgesia was introduced in the late 1990s as a technique
24to improve analgesia and reduce the incidence of opioid-related adverse events. The
rationale for this strategy is the achievement of suG cient analgesia through the additive
or synergistic e ects between di erent analgesics. This allows for a reduction in the doses
of these drugs and, thus, a lower incidence of adverse e ects. Currently, the American
25Society of Anesthesiologists Task Force on Acute Pain Management and the Agency for
26Health Care Policy and Research advocate the use of NSAIDs in a multimodal analgesic
approach for the management of acute pain. The practice guidelines for acute pain
management in the perioperative setting speci) cally state “unless contraindicated, all
patients should receive around-the-clock regimen of NSAIDs, coxibs, or
Currently, the administration of NSAIDs is one of the most common nonopioid analgesic
27techniques utilized for the management of postoperative pain. NSAIDs are useful as the
28sole analgesic after minor surgical procedures. Because of their ceiling e ect for
29analgesia, NSAIDs alone provide insuG cient analgesia after major surgery, but they
30demonstrate a signi) cant opioid-sparing e ect. The use of NSAIDs has become
increasingly popular because of the concern over opioid-related side e ects, such as
nausea, vomiting, sedation, pruritus, ileus, and urinary retention. Advantages of utilizing
NSAIDs as part of the perioperative “analgesic cocktail” include lack of sedation and
respiratory depression, a low abuse potential, and no interference with bowel or bladder
31function. In addition, unlike opioids (which are e ective for reducing spontaneous pain
at rest), NSAIDs demonstrate comparable eG cacy for pain both at rest and with
32movement, the latter of which may be more important for causing postoperative
33physiologic impairment. For these reasons, it is recommended that unless
contraindicated, nonselective NSAIDs should be considered the drugs of choice for the
26management of mild to moderate postoperative pain.
Nonselective NSAIDs encompass a chemically diverse group of compounds including
salicylates, proprionic acids, pyrazoles, acetic acids, oxicams, fenamates, and
naphthyl34alkanones (Table 9–1). These NSAIDs have been reported eG cacious in the
management of postoperative pain after dental, orthopedic, thoracic, abdominal, and
31,35gynecologic surgeries. Although all NSAIDs inhibit the COX enzyme, di erences in
their pharmacodynamic and pharmacokinetic properties may make some NSAIDs more

suitable as postoperative analgesics. Unfortunately, with the exception of dental surgery,
there are very few studies comparing the analgesic eG cacies of NSAIDs for postoperative
36pain. The Oxford League Table of analgesics may be used to indirectly compare the
eG cacy of these NSAIDs against each other. This Table is based on using comparisons of
di erent analgesics with placebo in similar clinical circumstances, with similar patients
included, similar pain measurement, and similar outcome measures, and deriving the
number-needed-to-treat (NNT) (Table 9–2). The eG cacy of analgesics is commonly
expressed as NNT, which represents the number of patients who need to receive the
active drug for one patient to achieve at least 50% relief of pain compared with placebo
37over a 4- to 6-hour treatment period. For example, an NNT of 2 means that for every
two patients who receive the drug, one patient will get at least 50% relief because of the
treatment (the other patient may or may not obtain relief, but it does not reach the 50%
level). The NNT is useful for comparison of relative eG cacy of analgesics because these
NNT comparisons are treatment-speci) c and are compared with placebo. NSAIDs do
extremely well in the single-dose postoperative comparison, with NNT values ranging
36between 1.6 and 3.4. For example, the NNT is 1.6 for ibuprofen 800 mg, 1.9 for
diclofenac 100 mg, 2.3 for naproxen 440 mg, 2.6 for ketorolac 10 mg, 2.7 for piroxicam
3620 mg, and 3.4 for intramuscular ketorolac 30 mg. At these doses, the majority of
NSAIDs are more e ective than single doses of either intramuscular morphine 10 mg or
meperidine 100 mg, which have an NNT of 2.9. However, these opioids are more
effective than both acetaminophen 1000 mg and aspirin 1000 mg, which have an NNT of
36,383.8 and 4.0, respectively.
Table 9–1 Nonsteroidal Anti-inflammatory Drugs
Generic Drug Name Trade Name
p-Aminophenol Derivatives
Acetaminophen Tylenol
Aspirin Dolobid
Diflunisal Trisalicylate, Trilisate
Choline magnesium trisalicylate Mono-Gesic
Proprionic Acids
Ibuprofen Motrin, Advil, Nuprin
Fenoprofen NalfonNaproxen Naprosyn, Anaprox, Alleve
Ketoprofen Orudis
Flurbiprofen Ansaid
Phenylbutazone Butazolidin
Acetic Acids
Indomethacin Indocin
Tolmetin Tolectin
Sulindac Clinoril
Diclofenac Voltaren, Cataflam
Etodolac Lodine
Ketorolac Toradol
Piroxicam Feldene
Meloxicam Mobic
Meclofenamic acid Meclomen
Mefenamic Ponstel
Nabumetone Relafen
Table 9–2 Oxford League Table of Analgesics in Acute Pain

Acetaminophen has demonstrated analgesic eG cacy for acute postoperative pain in a
39variety of analgesic models. A meta-analysis of 47 randomized, double-blind,
placebocontrolled clinical trials enrolling 4186 patients concluded that acetaminophen is an
39e ective analgesic for acute postoperative pain and gives rise to few adverse e ects.
Another meta-analysis of randomized, controlled trials of acetaminophen for
postoperative pain revealed that it induced a morphine-sparing e ect of 20% (9 mg) over
40the ) rst 24 hours postoperatively (95% con) dence interval [CI] –15 to –3 mg). A
recent qualitative review of acetaminophen, NSAIDs, and their combination concluded
that acetaminophen may provide analgesic eG cacy similar to that of other NSAIDs after
40major orthopedic surgery. It was concluded that acetaminophen may be a viable
alternative to NSAIDs in high-risk patients because of the lower incidence of adverse
41effects. Further, it may be appropriate to administer acetaminophen with an NSAID
42because these two analgesics may confer an additive or synergistic e ect.
Acetaminophen may be administered via either oral, rectal, or intravenous routes for the
management of postoperative pain. Oral doses of 650 mg have been shown to be more
e ective than doses of 300 mg; but little additional bene) t is seen at doses above 1000
43mg, indicating a possible ceiling e ect. The bioavailability of rectal acetaminophen is
more variable, approximately 80% of that of tablets and, the rate of absorption is slower,
44with maximum plasma concentration achieved about 2 to 3 hours after administration.
Doses of 40 to 60 mg/kg of rectal acetaminophen have been shown to have
opioid45sparing e ect in various postoperative pain models. Propacetamol is a prodrug of
acetaminophen that can be administered parenterally. The drug is completely hydrolyzed
within 6 minutes of administration, and 1 g of propacetamol yields 0.5 g of
46acetaminophen. Under these conditions, the pharmacokinetic pro) le is analogous to
that observed after the oral administration of acetaminophen 0.5 g, except for a
signi) cantly higher maximal plasma concentration as a result of the complete
46bioavailability of the injectable formulation. Similar to oral acetaminophen,
47intravenous propacetamol demonstrates a ceiling e ect for postoperative pain. The
maximum e ective intravenous dose of paracetamol is 5 mg/kg, resulting in a serum
47concentration of 14 mg/ml, which is a lower dose than previously suggested. After the
intravenous injection of propacetamol, acetaminophen easily crosses the blood-brain
46barrier, ensuring a central analgesic e ect. Injectable propacetamol has been shown to
reduce opioid consumption by about 35% to 45% in postoperative orthopedic pain
48-51studies and has demonstrated analgesic eG cacy similar to that of ketorolac after
52gynecologic surgery. Although widely utilized as an analgesic for decades in Europe,
propacetamol has not yet received approval by the U.S. Food and Drug Administration
Aspirin has been known to be an e ective analgesic for many years and is commonly

used in the treatment of both acute and chronic pain conditions. Aspirin has an
elimination half-life that increases from 2.5 hours at low doses to 19 hours at high
53doses. It is well absorbed in the stomach and small intestine, with peak blood level
achieved 1 hour after an oral dose. There is then rapid conversion of aspirin to salicylates
from a high ) rst-pass e ect, which occurs in the wall of the small intestine and the liver.
53The metabolic pathways follow ) rst-order and zero-order kinetics. A quantitative
systematic review of 72 randomized single-dose trials with 3253 patients given aspirin
38revealed a signi) cant analgesic e ect versus that of placebo. Aspirin demonstrated a
clear dose-response for pain relief, even though these were single-dose studies. Signi) cant
bene) t of aspirin over placebo was shown for aspirin 600/650 mg, 1000 mg, and 1200
38mg, with NNT for at least 50% pain relief of 4.4, 4.0, and 2.4, respectively. No
apparent ceiling e ect for analgesia was observed in this dose range. A comparison of the
analgesic eG cacy of aspirin with acetaminophen has revealed that these two drugs result
38in similar postoperative pain relief. These results are similar to those of a previous
study demonstrating that aspirin and acetaminophen are equianalgesic and, milligram
54per milligram, equipotent in a variety of pain models. Although it possesses similar
analgesic eG cacy to that of acetaminophen, the use of aspirin as a postoperative
analgesic has been limited by its greater side e ect pro) le. Unlike acetaminophen, the
55administration of aspirin causes a signi) cant inhibitory e ect on platelet function,
56resulting in greater perioperative blood loss. Aspirin, which irreversibly acetylates the
COX enzyme, causes inhibition of platelet aggregation for the lifespan of the platelet,
55which is 10 to 14 days. In contrast, nonselective NSAIDs reversibly inhibit the COX
enzyme, causing a transient reduction in the formation of thromboxane A (TXA ) and2 2
55inhibition of platelet activation, which resolves after most of the drug is eliminated. In
addition, even single doses of aspirin were associated with signi) cantly more drowsiness
and gastric irritation than placebo, with numbers-needed-to-harm of 28 and 38,
38respectively. For these reasons, the widespread use of aspirin as a postoperative
analgesic has been curtailed.
Ketorolac is currently the only parenteral NSAID for clinical analgesic use in the United
States. Ketorolac is almost entirely bound to plasma proteins (>99%), which results in a
small apparent volume of distribution with extensive metabolism by conjugation and
57excreted via the kidney. The analgesic e ect occurs within 30 minutes, with maximum
57e ect between 1 and 2 hours and duration of 4 to 6 hours. Ketorolac demonstrates
analgesia well beyond its anti-in ammatory properties, which are between those of
indomethacin and naproxen; but ketorolac can provide analgesia 50 times that of
57naproxen. Ketorolac has antipyretic e ects 20 times that of aspirin and, thus, can mask
a febrile response when administered during the postoperative period. Premarketing
clinical studies have demonstrated eG cacy of ketorolac 30 to 90 mg comparable with
those of morphine 6 to 12 mg, meperidine 50 to 100 mg, and propacetamol 2 g for the
58treatment of moderate postoperative pain. However, some studies have revealed that

ketorolac is ine ective as the sole postoperative analgesic in the management of
59,60moderate to severe postoperative pain. Similar to other NSAIDs, ketorolac
29demonstrates an analgesic ceiling e ect. Therefore, its eG cacy as an analgesic
monotherapy is usually insuG cient for moderately severe to severe pain after major
surgery. However, ketorolac can be utilized as an opioid-sparing technique in the
multimodal management of postoperative pain. Depending upon the type of surgery,
58ketorolac demonstrated an opioid-sparing e ect of a mean of 36%. Despite this
reduction in opioid use, the administration of ketorolac was not associated with a
concomitant reduction in opioid side e ects (e.g., nausea, vomiting, pruritus, urinary
Oral ketorolac was approved for use in the United States approximately 3 years after
61the parenteral form and has an eG cacy similar to that of naproxen and ibuprofen. The
recommended maximum total daily dose of oral ketorolac is 40 mg, and it is indicated
62only as a continuation of the parenteral therapy. The combined duration of use is not
62to exceed 5 days because of the increased risk of serious adverse events. The
appropriate analgesic dose of parenteral ketorolac is controversial. Since ketorolac has
been marketed, there have been reports of death owing to gastrointestinal and operative
63site bleeding. In the ) rst 3 years after ketorolac was approved in the United States (in
641990), 97 fatalities were reported. As a consequence, the drug’s license was suspended
65in Germany and France. In a response to these adverse events, the drug’s manufacturer
62recommended reducing the dose of ketorolac from 150 to 120 mg per day. The
European Committee for Proprietary Medicinal Products recommended a further maximal
66daily dose reduction to 60 mg for the elderly and 90 mg for the nonelderly. Currently,
29,67there is consensus that the maximum daily dose should be as low as 30 to 40 mg.
Further, ketorolac is contraindicated as a preemptive analgesic before any major surgery
and is contraindicated intraoperatively when hemostasis is critical because of the
62increased risk of bleeding.
COX-2–Specific Inhibitors (Coxibs)
Celecoxib was the ) rst COX-2–speci) c inhibitor (coxib) approved by the FDA in
December 1998, followed by rofecoxib in May 1999, and then valdecoxib in November
682001. Parecoxib (an injectable prodrug of valdecoxib), etoricoxib, and lumiracoxib
have not received FDA approval but are available in several countries outside the United
States. Numerous review articles have documented the eG cacy of coxibs for the
management of postoperative pain after dental, orthopedic, thoracic, gynecologic, and
69-75otolaryngologic surgeries. A systematic review of COX-2 inhibitors compared with
traditional NSAIDs concluded that these two classes of NSAIDs provided similar eG cacy
74for the management of postoperative pain.
Although nonspeci) c NSAIDs are considered to play an integral role in the
25,26management of postoperative pain, their routine use has been limited in the
perioperative setting because of concerns of platelet dysfunction, renal toxicity, and

28gastrointestinal toxicity. Although short-term use of NSAIDs for the management of
76acute pain does not seem to impair renal function, there are numerous reports of
NSAID-induced renal failure when these drugs are utilized for the perioperative
77-82management of pain. Similarly, there have been numerous reports of
gastrointestinal ulceration or bleeding associated with brief exposure to NSAIDs for the
83-87perioperative management of pain. Finally, the use of traditional NSAIDs may result
in an increased incidence of perioperative blood loss and blood transfusion requirements,
resulting in increased morbidity and mortality after a variety of surgical
99-101procedures. Because these major side e ects are related to the inhibition of the
COX-1 enzyme, the perioperative use of coxibs appears to be a safer alternative to
74,102traditional NSAIDs for the perioperative management of pain. The speci) city of
103COX-2–selective inhibitors accounts for their safer gastrointestinal pro) le and lack of
55,68antiplatelet activity relative to nonspecific NSAIDs.
The coxibs pose a real and attractive alternative to traditional NSAIDs in cases in
which bleeding is a concern, including total joint arthroplasty and tonsillectomy. Prior to
the introduction of coxibs, many patients undergoing elective total joint arthroplasty
104were instructed to discontinue their use of NSAIDs 7 to 10 days prior to surgery.
Continuing conventional NSAIDs before total joint arthroplasty has been associated with
a twofold increase in the incidence of perioperative bleeding, resulting in higher
90transfusion requirements. The use of NSAIDs has been associated with other
postoperative complications, including wound hematoma, upper gastrointestinal tract
89bleeding, and hypotension. The likelihood of developing these complications was found
to be 5.8 times greater for patients using NSAIDs 24 hours before surgery than for those
89without such usage. We have observed that discontinuing NSAIDs before total joint
arthroplasty results in an arthritic are, not only in the operative joint but also in other
104arthritic joints, leading to increased preoperative pain. Increased pain before total
joint arthroplasty is the leading cause for increased postoperative pain, prolonged
105hospital admission, and impaired rehabilitation. The administration of perioperative
coxibs for total joint arthroplasty has demonstrated a reduction in perioperative pain and
improvement in outcomes without an added risk of increased perioperative
The use of traditional NSAIDs for tonsillectomy is also associated with an increased risk
101for perioperative bleeding and reoperation for bleeding. A meta-analysis of
randomized, controlled trials involving the e ects of NSAIDs on bleeding after
tonsillectomy concluded that “the use of NSAID therapy after tonsillectomy should be
101abandoned both at the hospital and at home.” However, these authors did not
account for the use of coxibs in their meta-analysis. A subsequent study evaluated the
safety and eG cacy of administering rofecoxib 1 mg/kg prior to pediatric
107tonsillectomy. This study revealed a signi) cant reduction in postoperative pain,
opioid use, and the incidence of postoperative nausea and vomiting without an increase
in intraoperative surgical bleeding or in the likelihood of reoperation for bleeding. These

68-75data support previous ) ndings that coxibs do not increase perioperative blood loss
and that these NSAIDs may prove useful for the management of post-tonsillectomy pain.
In an attempt to determine whether an individual COX-2–selective inhibitor possesses
greater analgesic eG cacy for acute postoperative pain, several meta-analyses have been
108-111performed in which the NNT for one patient to achieve 50% pain relief was
calculated. In these studies, the NNTs for the COX-2 inhibitors valdecoxib 40 mg,
rofecoxib 50 mg, and parecoxib 40 mg were 1.6, 1.9, and 2.2, respectively. These values
36are similar to those reported for the traditional NSAIDs. The only COX-2 inhibitor to
perform less well than the other coxibs or most traditional NSAIDs was celecoxib 200 mg
110with an NNT of 4.5. However, subsequent to this meta-analysis, celecoxib received
approval by the FDA for the management of acute pain. The celecoxib dose for acute
pain is 400 mg followed by a 200-mg dose within the ) rst 24 hours then 200 mg twice
112daily on subsequent days. Because celecoxib is currently the only selective COX-2
inhibitor available in the United States, future randomized, controlled clinical trials
utilizing these recommended doses are necessary to determine the analgesic eG cacy of
this NSAID for acute pain postoperative management.
Celecoxib has approval for the relief of pain from osteoarthritis, rheumatoid arthritis,
acute pain, and dysmenorrhea and to reduce the number of adenomatous colorectal
112polyps in familial adenomatous polyposis. The concomitant administration of
celecoxib with aluminum- or magnesium-containing antacids results in a reduction of
plasma levels of this NSAID. Peak plasma levels occur 3 hours after oral administration,
19and the drug crosses into the central spinal uid. Celecoxib is 97% protein bound, with
an apparent volume of distribution of 400 L, suggesting extensive distribution into
112tissues. It is metabolized via cytochrome P-450 2C9 and eliminated predominantly by
the liver. It is not indicated for pediatric use and is a category C drug for pregnancy.
Celecoxib can increase plasma lithium levels, and the concomitant administration of
di ucan can increase plasma levels of celecoxib. The drug has a half-life of about 11
112hours. Adverse events noted in the various clinical trials include headache, edema,
dyspepsia, diarrhea, nausea, and sinusitis. It is contraindicated in patients who have a
sulfonamide allergy or a known hypersensitivity to aspirin or other NSAIDs. Celecoxib has
been shown to have no e ect on platelet function measured by serum thromboxane
113production and ex vivo platelet aggregation. In fact, celecoxib in doses of 1200
mg/day administered for 10 consecutive days in healthy adults demonstrated no effect on
113platelet aggregation or bleeding time.
Previous studies have shown analgesic eG cacy with the perioperative administration of
110,114-117celecoxib 200 mg for dental, orthopedic, and otolaryngologic surgeries.
However, these clinical investigations may have underestimated the analgesic eG cacy of
celecoxib because they did not utilize the appropriate dose for postsurgical pain. The
need for an initial loading dose of celecoxib is related to its large volume of distribution
118(400 L). In a dose-ranging study after otolaryngologic surgery, celecoxib 400 mg was

more e ective than 200 mg in reducing severe postoperative pain and the need for rescue
analgesic medication in the postoperative period. However, even this study was awed
because these investigators failed to administer a subsequent dose of celecoxib 200 mg
within the ) rst 24 hours postoperatively. The ) rst clinical investigation to document the
analgesic eG cacy of celecoxib administered for postoperative pain management
according to the current acute pain guidelines demonstrated a 31% reduction in 24-hour
119morphine use and a signi) cant decrease in pain scores. This represents a signi) cant
improvement in analgesic eG cacy compared with a previous study in which only a 9%
reduction in morphine use was reported with the administration of a single 200-mg dose
114of celecoxib prior to the same surgical model. In addition to lower morphine use,
celecoxib administration resulted in signi) cantly lower pain scores at all postoperative
time intervals except at 12 and 24 hours postsurgery, which coincides with the time at
which this drug needs to be redosed.
It is common belief that parenteral NSAIDs are more eG cacious in the management of
acute pain than orally administered NSAIDs. Many physicians continue to administer
NSAIDs via the parenteral route even though patients are tolerating oral intake after
surgery. Reasons for choosing the parenteral route are pharmacokinetic based, that is, the
rate of drug absorption may a ect the eG cacy and onset of analgesia. However, one
meta-analysis comparing NSAIDs administered by di erent routes for the management of
120acute and chronic pain failed to detect any di erence in analgesic eG cacy. The
intramuscular and rectal routes were associated with more local adverse e ects, and the
120intravenous route resulted in a greater risk of postoperative bleeding. The risk of
gastrointestinal toxicity was similar with the administration of NSAIDs by either the
parenteral or the oral route. The authors concluded that there is a strong argument to
administer NSAIDs via the oral rather than the parenteral route for the management of
120postoperative pain as soon as patients are tolerating oral intake.
In an attempt to provide a peripheral analgesic e ect, some investigators have utilized
NSAIDs administered via either topical application or local wound in) ltration for the
management of acute pain. These routes provide for high concentrations of these agents
at the site of the in ammatory process, with the potential for a more e ective reduction
of in ammation. Further, there is a potential for fewer side e ects because lower doses of
121the drug may be used, resulting in lower plasma concentrations of the NSAID. It has
been demonstrated that even without a reduction in dose, the topical administration of
NSAIDs results in much lower plasma concentrations of the drug compared with the same
122,123dose of NSAID administered orally. For these reasons, the topical administration
of NSAIDs demonstrates a lower incidence of adverse events, including gastrointestinal
124toxicity, compared with the oral route. A quantitative systematic review of topical
125NSAIDs for acute pain con) rmed the bene) t of this route of administration. After a
review of the literature, it was concluded that both the topical and the oral routes
provided comparable analgesic eG cacy for acute pain. Further, the topical route was