Current Therapy in Pain E-Book
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Current Therapy in Pain E-Book


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1662 pages

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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)


Publié par
Date de parution 21 décembre 2008
Nombre de lectures 2
EAN13 9781437711172
Langue English
Poids de l'ouvrage 3 Mo

Informations légales : prix de location à la page 0,0416€. Cette information est donnée uniquement à titre indicatif conformément à la législation en vigueur.


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 York
Saunders Elsevier
1600 John F. Kennedy Boulevard
Ste 1800
Philadelphia, PA 19103-2899
Copyright © 2009 by Saunders, an imprint of Elsevier Inc.
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (+1) 215 239 3804 (US) or (+44) 1865 843830 (UK); fax: (+44) 1865 853333; e-mail: . You may also complete your request on-line via the Elsevier website at .

Knowledge and best practice in this field 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 1
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.

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 PERIPHERAL NEUROPATHY; PAIN IN CHILDREN; BOTULINUM TOXINS FOR THE TREATMENT OF PAIN; EPIDURAL STEROID INJECTIONS; RADIOFREQUENCY TREATMENT; CRYOANALGESIA FOR CHRONIC PAIN

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, Massachusetts, PAIN IN THE PALLIATIVE CARE POPULATION

Sanjeev Agarwal, MD, Assistant Professor, and Director, Interventional Physiatry, SUNY Downstate Medical Center, Brooklyn, New York, STEROIDS; SYMPATHETIC BLOCKADE

Phillip J. Albrecht, PhD, Assistant Professor, Center for Neuropharmacology and Neuroscience, Albany Medical College; Integrated Tissue Dynamics, LLC, Albany New York, COMPLEX REGIONAL PAIN SYNDROME PATHOPHYSIOLOGY

Catalina Apostol, MD, Resident in Pain/Anesthesiology, Department of Anesthesiology, University of Miami, Miami, Florida, BOTULINUM TOXINS FOR THE TREATMENT OF PAIN

Charles E. Argoff, MD, Professor of Neurology, Albany Medical College; Director, Comprehensive Pain Program, Albany Medical Center, Albany, New York, NEUROPATHIC PAIN-DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THERAPY; ANTIDEPRESSANTS; BOTULINUM TOXINS FOR THE TREATMENT OF PAIN

Joseph F. Audette, MA, MD, Assistant Professor, Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, Massachusetts, COMPLEMENTARY AND ALTERNATIVE MEDICINE FOR NONCANCER PAIN

Mark L. Baccei, PhD, Research Assistant Professor, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, PATHOPHYSIOLOGY OF PAIN

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, NEUROPATHIC PAIN-DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THERAPY

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, HEADACHES OTHER THAN MIGRAINE; TRIGEMINAL NEURALGIA

Jeffrey R. Basford, MD, PhD, Professor of Physical Medicine and Rehabilitation, Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, Minnesota, TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION

Allison Baum, DPT, Spinal Cord Injury Peer Mentor Coordinator, St. Charles Hospital and Rehabilitation Center, Port Jefferson, New York, PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT

Joseph M. Bellapianta, MD, MS, Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York, HAND PAIN; FOOT PAIN

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, Norway, ASSESSMENT OF PAIN IN THE NONVERBAL AND/OR COGNITIVELY IMPAIRED OLDER ADULT

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 IMAGING IN PAINFUL STATES: EXPERIMENTAL AND CLINICAL 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, New York, ASSESSMENT OF PAIN IN OLDER ADULTS

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, BACK PAIN

Juan Cata, MD, Resident, Institute of Anesthesiology, Critical Care, and Comprehensive Pain Management, Cleveland Clinic, Cleveland, Ohio, INTERPLEURAL ANALGESIA

Brian D. Cauley, MD, MPH, Resident, Department of Anesthesiology and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, POSTHERPETIC NEURALGIA

Lucy Chen, MD, Instructor, Harvard Medical School; Attending Physician, Massachusetts General Hospital, Boston, Massachusetts, OPIOID TOLERANCE, DEPENDENCE, AND HYPERALGESIA

Jianguo Cheng, MD, PhD, Staff, Department of Pain Management, Institute of Anesthesiology, Critical Care, and Comprehensive Pain Management, Cleveland Clinic, Cleveland, Ohio, INTERPLEURAL ANALGESIA

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, Baltimore, Maryland, PELVIC PAIN; POSTHERPETIC NEURALGIA; COMPLEX REGIONAL PAIN SYNDROME: TREATMENT APPROACHES

Daniel Ciampi de Andrade, 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 IMAGING IN PAINFUL STATES: EXPERIMENTAL AND CLINICAL PAIN

Eli Cianciolo, MD, Clinical Instructor and Pain Medicine Fellow, Harvard Medical School, and Massachusetts General Hospital, Boston, Massachusetts, NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CYCLOOXYGENASE-2 INHIBITORS

Daniel Clayton, MD, PhD, Resident, Division of Neurosurgery, Duke University Medical Center, Durham, North Carolina, NEUROSURGICAL TREATMENT OF PAIN

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 INJECTIONS

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 ADHESIOLYSIS


Timothy R. Deer, MD, President and Chief Executive Officer, The Center for Pain Relief; Clinical Professor, West Virginia University, Charleston, West Virginia, EPIDEMIOLOGY OF COMPLICATIONS IN INTERVENTIONAL PAIN MANAGEMENT

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 EPIDURAL ANALGESIA; CONTINUOUS PERIPHERAL NERVE CATHETER TECHNIQUES

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 ANALGESIA

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 York, POST AMPUTATION PAIN DISORDERS; POSTSTROKE PAIN

Demetri Economedes, DO, Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York, HAND PAIN

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-AGONISTS

Nasr Enany, MD, Assistant Professor and Attending Anesthesiologist, University of Cincinnati, Cincinnati, Ohio, SYMPATHETIC BLOCKADE

Jonathan Epstein, MD, MA, Fellow, Obstetric Anesthesia, Mount Sinai Medical Center, New York, New York, TRAMADOL

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, Massachusetts, COMPLEMENTARY AND ALTERNATIVE MEDICINE FOR NONCANCER PAIN

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, Florida, PAINFUL DIABETIC PERIPHERAL NEUROPATHY

Richard Field, MD, Pain Fellow, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts, RADIOFREQUENCY TREATMENT

Nanna Brix Finnerup, MD, Associate Research Professor, Aarhus University, Aarhus, Denmark, SPINAL CORD INJURY

Colleen M. Fitzgerald, MD, Assistant Professor, Feinberg School of Medicine, Northwestern University; Medical Director, Women’s Health Rehabilitation, Rehabilitation Institute of Chicago, Chicago, Illinois, FEMALE PERINEAL/PELVIC PAIN: THE REHABILITATION APPROACH

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, DIAGNOSIS AND TREATMENT OF FACET-MEDIATED CHRONIC LOW BACK PAIN

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, INTERDISCIPLINARY MANAGEMENT FOR COMPLEX REGIONAL PAIN SYNDROME

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, NEUROPATHIC PAIN: IS THE EMPEROR WEARING CLOTHES?

Christina K. Hynes, MD, Clinical Instructor, Feinberg School of Medicine, Northwestern University; Attending Physician, Rehabilitation Institute of Chicago, Chicago, Illinois, FEMALE PERINEAL/PELVIC PAIN: THE REHABILITATION APPROACH

Kenneth C. Jackson, II, PharmD, Associate Professor, Pacific University School of Pharmacy; Associate Editor, Journal of Pain and Palliative Care Pharmacotherapy, Hillsboro, Oregon, OPIOID PHARMACOTHERAPY

Chauncey T. Jones, MD, Resident, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, COMPLEX REGIONAL PAIN SYNDROME: TREATMENT APPROACHES

Douglas Keene, MD, Director of Pain Management, Department of Anesthesia, Milton Hospital, Milton, Massachusetts; Co-founder, Boston PainCare, Waltham, Massachusetts, RADIOFREQUENCY TREATMENT

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 DOCUMENTATION TOOLS FOR OPIOID THERAPY; PAIN IN THE SUBSTANCE ABUSE POPULATION

Jan Kraemer, MD, Clinical Fellow, Harvard Medical School, Boston, Massachusetts, HEADACHES OTHER THAN MIGRAINE

Michael A. Krieves, BS, Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York, HIP PAIN; KNEE PAIN

Clete 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


Lori A. Lavelle, DO, Staff Physician, Altoona Arthritis and Osteoporosis Center, Duncansville, Pennsylvania, RHEUMATOID ARTHRITIS; INTRA-ARTICULAR INJECTIONS

William F. Lavelle, MD, Assistant Professor, Department of Orthopaedic Surgery, SUNY Upstate Medical University, Syracuse, New York, HAND PAIN; BACK PAIN; HIP PAIN; KNEE PAIN; FOOT PAIN; RHEUMATOID ARTHRITIS; MYOFASCIAL TRIGGER POINTS; INTRA-ARTICULAR INJECTIONS

Andrew Linn, MD, Clinical Fellow in Anesthesia, Harvard Medical School, and Beth Israel Deaconess Medical Center, Boston, Massachusetts, TRIGEMINAL NEURALGIA

Dave Loomba, MD, Assistant Professor, University of California, Davis, Sacramento; Anesthesiologist, Enloe Medical Center, Chico, California, SACROILIAC JOINT PAIN

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, Massachusetts, PAIN AND PAIN MANAGEMENT RELATED TO HIV INFECTION

Gagan 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 TOLERANCE, DEPENDENCE, AND HYPERALGESIA

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, LUMBAR SPINAL STENOSIS: CURRENT THERAPY AND FUTURE DIRECTIONS; DIAGNOSIS AND TREATMENT OF FACET-MEDIATED CHRONIC LOW BACK PAIN

Eric M. May, MD, Assistant Professor of Anesthesiology, University of Missouri-Kansas City; Staff Anesthesiologist, Saint Luke’s Hospital, Kansas City, Missouri, CONTINUOUS PERIPHERAL NERVE CATHETER TECHNIQUES


James McLean, MD † , Pain Fellow, Rehabilitation Institute of Chicago; Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT

Sangeeta R. Mehendale, MD, PhD, Research Associate, Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, GASTROINTESTINAL DYSFUNCTION WITH OPIOID USE

Harold 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 TOXINS FOR THE TREATMENT OF PAIN

Mila Mogilevsky, DO, PT, Resident Physician, Rehabilitation Institute of Chicago, Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, Illinois, PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT

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 IMAGING IN PAINFUL STATES: EXPERIMENTAL AND CLINICAL PAIN


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, Maryland, A MECHANISM-BASED APPROACH TO PAIN PHARMACOTHERAPY: TARGETING PAIN MODALITIES FOR OPTIMAL TREATMENT EFFICACY

Lida Nabati, MD, Instructor of Medicine, Harvard Medical School; Attending Physician, Division of Palliative Care, Dana-Farber Cancer Institute, Boston, Massachusetts, PAIN IN THE PALLIATIVE CARE POPULATION

Srdjan 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 RELATED TO HIV INFECTION

Lisa J. Norelli, MD, MPH, MRCPsych, Assistant Professor of Psychiatry, Albany Medical College; Director of Psychiatry, Capital District Psychiatric Center, Albany, New York, HYPNOTIC ANALGESIA

Akiko Okifuji, PhD, Professor of Anesthesiology, and Attending Psychologist, Pain Management Center, University of Utah, Salt Lake City, Utah, PSYCHOLOGICAL ASPECTS OF PAIN

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, North Carolina, SPINAL CORD STIMULATION FOR THE TREATMENT OF CHRONIC INTRACTABLE PAIN; NEUROSURGICAL TREATMENT OF PAIN

Joshua Pal, MD, Clinical Fellow, Harvard Medical School, Boston, Massachusetts, HEADACHES OTHER THAN MIGRAINE

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, NEUROPATHIC PAIN-DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THERAPY; TRAMADOL

Amar Parikh, Research Assistant, Albany Medical College, Albany, New York, POST AMPUTATION PAIN DISORDERS

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, PAIN IN THE SUBSTANCE ABUSE POPULATION

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, COMPLEMENTARY AND ALTERNATIVE MEDICINE FOR NONCANCER PAIN

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 Jersey, OROFACIAL PAIN

Annie Philip, MD, Assistant Professor, Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York, DIAGNOSIS AND TREATMENT OF FACET-MEDIATED CHRONIC LOW BACK PAIN

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, Florida, CRYOANALGESIA FOR CHRONIC PAIN

Lynn Rader, MD, Clinical Instructor, Feinberg School of Medicine, Northwestern University; Attending Physician, Rehabilitation Institute of Chicago, Chicago, Illinois, PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT

Lakshmi Raghavan, PhD, Associate Director, Research and Development, Vyteris Corporation, Inc. Fair Lawn, New Jersey, PAIN IN CHILDREN

Rakesh Ramakrishnan, BS, Department of Orthopaedic Surgery, Albany Medical Center, Albany, New York, HIP PAIN; KNEE PAIN

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, Connecticut, MIGRAINE HEADACHES

Rahul Rastogi, MD, Assistant Professor, Washington University in St. Louis; Assistant Professor and Attending Anesthesiologist, Barnes-Jewish Hospital, St. Louis, Missouri, SYMPATHETIC BLOCKADE

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 OF COX-2 AGENTS

Frank L. Rice, PhD, Professor, Center for Neuropharmacology and Neuroscience, Albany Medical College; Integrated Tissue Dynamics, LLC, Albany, New York, COMPLEX REGIONAL PAIN SYNDROME PATHOPHYSIOLOGY

Melissa A. Rockford, MD, Assistant Professor of Anesthesiology, University of Kansas Medical Center, University of Kansas School of Medicine, Kansas City, Kansas, PERIOPERATIVE EPIDURAL ANALGESIA

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 RECEPTOR ANTAGONISTS

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, CRYOANALGESIA FOR CHRONIC PAIN

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, OSTEOARTHRITIS: ETIOLOGY, PATHOGENESIS, AND TREATMENT

Thomas T. Simopoulos, MD, Instructor in Anaesthesia, Harvard Medical School; Director of Interventional Pain Management, Beth Israel Deaconess Medical Center, Boston, Massachusetts, FAILED BACK SURGERY SYNDROME

Jeremy C. Sinkin, BA, Department of Neurosurgery, University of Rochester School of Medicine and Dentistry, Rochester, New York, LUMBAR SPINAL STENOSIS: CURRENT THERAPY AND FUTURE DIRECTIONS

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, PSYCHOLOGICAL ASPECTS OF PAIN

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, New York, NEUROPATHIC PAIN—DEFINITION, IDENTIFICATION, AND IMPLICATIONS FOR RESEARCH AND THERAPY; POTENTIAL DOCUMENTATION TOOLS FOR OPIOID THERAPY; POST AMPUTATION PAIN DISORDERS; COMPLEX REGIONAL PAIN SYNDROME PATHOPHYSIOLOGY; PAIN AND SLEEP; OPIOIDS ISSUES; ACETAMINOPHEN; ANTIDEPRESSANTS; GLUTAMATE RECEPTOR ANTAGONISTS; BOTULINUM TOXINS FOR THE TREATMENT OF PAIN; CRYOANALGESIA FOR CHRONIC PAIN

Paul E. Spurgas, MD, Associate Professor of Neurosurgery, Division of Neurosurgery, Albany Medical Center, Albany, New York; Temple University, Philadelphia, Pennsylvania, VERTEBROPLASTY AND KYPHOPLASTY

Steven C. Stain, MD, Neil Lempert Professor, and Chair, Department of Surgery, Albany Medical College; Chief of Surgery, Albany Medical Center Hospital, Albany, New York, ABDOMINAL PAIN

Steven Stanos, DO, Assistant Professor, Feinberg School of Medicine, Northwestern University; Medical Director, Rehabilitation Institute of Chicago, Chicago, Illinois, PHYSICAL MEDICINE APPROACHES TO PAIN MANAGEMENT

Roland Staud, MD, Professor of Medicine, University of Florida, Gainesville, Florida, FIBROMYALGIA SYNDROME

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 PAIN; ELBOW PAIN

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 FOR THE TREATMENT OF PAIN

Deirdre M. Walsh, DPhil, BPhysio, Professor of Rehabilitation Research, Health and Rehabilitation Sciences Research Institute, University of Ulster, Newtownabbey, County Antrim, Northern Ireland, United Kingdom, TRANSCUTANEOUS ELECTRICAL NERVE STIMULATION

Chris Warfield, BA, Research Assistant, Arnold Pain Management Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, COGNITIVE THERAPY FOR CHRONIC PAIN

Ajay D. Wasan, MD, MSc, Assistant Professor, Harvard Medical School; Departments of Anesthesiology and Psychiatry, Brigham and Women’s Hospital, Boston, Massachusetts, ANTIDEPRESSANTS

Lynn R. Webster, MD, FACPM, FASAM, Medical Director, Lifetree Clinical Research and Pain Clinic, Salt Lake City, Utah, PAIN AND SLEEP

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, Massachusetts, COGNITIVE THERAPY FOR CHRONIC PAIN

James P. Wymer, MD, PhD, Assistant Professor of Neurology, Albany Medical College; Upstate Clinical Research, Albany, New York, GLUTAMATE RECEPTOR ANTAGONISTS

Chun-Su Yuan, MD, PhD, Cyrus Tang Professor, Department of Anesthesia and Critical Care, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, GASTROINTESTINAL DYSFUNCTION WITH OPIOID USE

Jun-Ming Zhang, MD, MSc, Associate Professor and Director of Research, Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, PATHOPHYSIOLOGY OF PAIN; STEROIDS; NONSTEROIDAL ANTI-INFLAMMATORY DRUGS AND CYCLOOXYGENASE-2 INHIBITORS

YiLi Zhou, MD, PhD, Courtesy Clinical Assistant Professor, University of Florida; Medical Director, Comprehensive Pain Management of North Florida, Gainesville, Florida, DIAGNOSIS AND MINIMALLY INVASIVE TREATMENT OF LUMBAR DISCOGENIC PAIN

† Deceased
The International Association for the Study of Pain (IASP) has defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or defined in terms of such damage”. Donald Price in his 1999 book Psychological Mechanisms of Pain and Analgesia by IASP Press proposed an alternative definition, arguing that the IASP definition 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 suffering due to pain which may dramatically affect 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 Refined 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 suffers from chronic pain as defined by the broad IASP definition and that 10-20% experience chronic pain when measures of clinical significance are added to the definition. They further state that the incidence of chronic pain (though difficult 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 variable.
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) inflammatory 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-inflammatory processes may exist for certain pro-inflammatory/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 specifically 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 efforts, too many people continue to exist with horrific pain and suffering, some who have been helped a little, and some who have not been helped at all. The field 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 field 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 field 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 not comprehensive 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 future.
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.

The editor would like to thank and acknowledge the enormous efforts of Pya Seidner who helped to bring this project to fruition.
The editor would like to acknowledge and thank the Reflex 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 flooring 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 shoulder-shrugging or avoidance of the subject when medical trainees ask me those difficult 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 management?
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 field to do that all-important and selfless 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, Utah
Table 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 Pain
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
Chapter 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 Syndrome
Chapter 42: Lumbar Spinal Stenosis: Current Therapy and Future Directions
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 Cyclooxygenase-2 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 Pain
Chapter 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 Pain
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 Analgesia
Chapter 89: Epidemiology of Complications in Interventional Pain Management

Harold Merskey

Taxonomy is the theory and practice of classification. For an ideal classification, each item to be considered should be independent of all other items so that it stands in its own place in the classification. For example, if we wish to classify peoples’ names for a telephone directory, each name must represent a separate and distinguishable item. The classification 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 numeric postscript as John A. Smith 1 , John A. Smith 2 , John A. Smith. 3 That provides a perfect classification useful for the purpose for which it is intended and of little or no interest besides.


• Comprehensive
• Specific place for each item
Natural classifications 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 classification also. Each element has a place of its own into which it fits and no other element with which it can be confused. Evolutionary classifications of flora and fauna similarly achieve great success, although disputes may arise in marginal cases ( Box 1–2 ).





Telephone directory
Medical classification lacks the rigor of either the telephone directory or the periodic table. It is exceptionally untidy, but it is taken to reflect 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. Classification may then be bedeviled by an argument about the criteria that apply to a particular diagnosis, for example, what is Cervicogenic Headache? What is the difference 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 classification and may or may not be illuminating, but resolving them is not part of the primary function of a classificatory system. Classification 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 classifier is simply to make sure that individuals can identify and locate types of objects or events. The classifier is not required to establish a true “meaning.” 1 Thus, if physicians in different parts of the world wish to exchange information about headache, it is not necessarily important to resolve, first, whether Migraine should or should not include phonophobia in its classification. 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 different 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 different 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 classificatory slot and which criteria go into another classificatory 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 classification 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 classification needs to proceed on the basis of information that is largely agreed and to define 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 classifications vary enormously but are all, or nearly all, illogical. In the International Classification of Diseases and Related Health Problems , 10th edition (ICD-10), 2 for example, we find that conditions are classified 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 affective 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 TR, at present 3 ) as “Axis I Type Disorders,” and Personality Disorders are classified 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 classified 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 classification, that is, the simplest and least complex description of phenomena, conditions used to be classified simply as “Symptoms, Signs and Ill-Defined Conditions” and are now classified as Symptoms and Signs, which actually constitute a group on their own in the ICD-10. 2 Not only illness is classified in medical lists. There was also a code in ICD-9 4 : 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 defined first 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 find “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 defined in terms of 5 subtypes on a biochemical and therapeutic basis. Among Musculoskeletal conditions, we have “Fibromyalgia” defined 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 Psychiatric Association’s DSM-III 5 provided at least five different Axes on which conditions might be classified including Axis I: Clinical Disorders; Axis II: Personality Disorders, Mental Retardation, or Specific 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 classification 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 classification cannot be provided on a theoretical basis is to provide agreed operational definitions. 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 classification 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 classifications that will code the varieties and degrees of a single diagnostic category such as stroke, 6 and there are also classifications that cover not just the type of illness or condition examined but simply the reason for consultation. Thus, the ICCPC, the International Classification of Conditions in Primary Care 7 does not classify diseases but rather the reason for contact between the family practitioner and her or his patient. Such a classification will include the reason for a patient being in the doctor’s office (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 classifiable and can be examined for whatever statistical purpose desired. The one thing classification 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 classification in the field of pain.” 1 A classification of pain was prepared originally for the International Association for the Study of Pain, and first published in 1986, 8 with a second edition in 1994. The aim of the classification is described in the introduction to the 1994 volume 9 as being to classify the major causes of chronic pain and to organize descriptions of the syndromes. It turned out slightly differently.
At first, it was not felt possible nor desirable to classify all painful conditions. A good classification 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 classification 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 classification would be to provide a means of communication between specialists in the field 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 different person would call by the same name, even internationally. A few types of acute pain were admitted to the classification 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 difficult 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 first means recognizing that the empirical methods of medicine are not yet good enough to provide etiologic classification, 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 classification was detailed and well worked out, there was insufficient agreement on etiology to make that approach satisfactory for pain as a whole. An impressive classification had actually been developed by the late Dr. John Bonica in his classic work, The Management of Pain . 10 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 first 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 first 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 classification 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 first four Axes of a pain classification had emerged as regions, systems, temporal characteristics, and intensity combined with duration since onset. Finally, room was left for etiology, and that was classified as genetic or congenital: trauma; surgery; infective or parasitic; inflammatory 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
IASP, International Association for the Study of Pain. 8
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 reflects 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 reflect 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 satisfies 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 five 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 classifications could theoretically use these additional codes. In order to discriminate between conditions occupying the same five 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 fibromyalgia 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 classification were conveniently identified through it by members of the IASP who were able to refer to relevant sections of the classification 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 “hysteria.”

The uses of classification 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 significance. Given the structured method, we can proceed to identify the subordinate phenomena that may lead to a more refined diagnosis. Even when there is a refined 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 diagnosis


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.

Jun-Ming Zhang, Mark L. Baccei

Pain is defined 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 specific nociceptors ( nociceptive pain ). However, it may also result from a lesion or dysfunction of peripheral afferent fibers 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 classified 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 finger 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 benefit 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
• Protective function
• Can be differentiated from touch
• Transient
• Well localized
• C- and Aδ-fiber–mediated
• Increased activity, wide dynamic range neurons
• Opioid sensitive
• Pain caused by nerve injury
• Spontaneous, evoked activity
• Develops in days or months
• Associated with inflammation, neuropathy
• Associated with peripheral and central sensitization
• Pain outlasts duration of the stimulus
• Pain sensed in noninjured areas
• Elicited by Aβ (?) as well as C and Aδ fibers
• 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; reflex 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 defined as pain that persists without any identifiable 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 first step in this process involves the transduction of the sensory stimulus (which can be mechanical, thermal, or chemical) into an electrical potential by first-order afferent neurons in the DRG located external to the spinal cord. These neurons express specialized receptors at their distal ends that respond to specific 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 significant 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 fibers (which conduct impulses at 2–30 m/sec) or small unmyelinated C-fibers (with conduction velocities of < 2 m/sec).
The signals carried by all three types of sensory afferents 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 C-fibers in the dorsal horn. This is believed to underlie the effectiveness 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-fiber nociceptive neurons (sensitization), which can be caused by chronic inflammation or other chronic noxious stimulation of C-fibers. 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 the perception 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 pathway Crosses the midline and ascends on the opposite side of 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 pain. Spinoreticular pathway Ascends on both sides of the spinal cord to the 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 emotion). Dorsal column pathway Transmits visceral nociception (as well as somatic touch and position sense) to the thalamus. Spinomesencephalic tract Travels with the spinotectal tract to the periaqueductal 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 pathway A recently described route; does not synapse in the 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, toxic)
• Neuroma (amputation, nerve transection) Dorsal root ganglion
• Compression (disk, tumor, scar tissue)
• Root avulsion
• Inflammation (postherpetic neuralgia) Spinal cord, brainstem, thalamus, cortex
• Spinal cord, brainstem, thalamus, 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 with normal, uninjured axons. 1 However, this is a common phenomenon after the peripheral axons are injured and reflects underlying alterations in the complement of voltage-gated ion channels expressed by DRG neurons. 2 - 10 There is now compelling evidence that the expression of sodium channel subtypes (e.g., Na v 1.3, Na v 1.7, Na v 1.8, and Na v 1.9) is dramatically altered by nerve injury and may account for the increased excitability of neuropathic DRG neurons in models of chronic pain. 11 - 13 The accumulation of Na v 1.3 channels in the injured DRG somata and neuroma may play a significant role in the development and maintenance of ectopic discharges. Meanwhile, the loss of sodium currents mediated by the Na v 1.8, and Na v 1.9 subtypes in injured DRG neurons leads to a 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 v 1.3), thus increasing 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 significantly 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 alterations in the expression of voltage-sensitive Ca 2+ 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 significant 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, among other mechanisms, an interaction with Ca 2+ 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 exacerbated by cold and gentle mechanical stimulation. 14 Clinically, SMP appears to be a significant 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 afferent sensory nervous system and the efferent 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 inflamed 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 identified 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 efferent fibers extensively sprout into both DRG and spinal nerves. Sprouting fibers sometime form distinctive basket-like webs (sympathetic baskets) or rings wrapping around medium and large DRG neurons. 15 Although it is currently unclear what triggers the sprouting of sympathetic nerve fibers in the ganglia, recent studies 16 suggest that sympathetic sprouting is associated with the inflammatory responses within the axotomized DRG and may be mediated by abnormal spontaneous activity of the DRG neurons.

Inflammatory Cytokines and Chemokines
Proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1 and IL-6, and chemokines (e.g., monocyte chemoattractant protein-1 [MCP-1]) 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 specific 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-fiber nociceptors, may lead to sensitization of dorsal horn neurons (i.e., “central sensitization”). 17 This can result in the following alterations in the physiologic properties of dorsal horn neurons: (1) increased size of the receptive field (i.e., the area of the body that, when stimulated, evokes action potential firing in the cell); (2) lower thresholds; neurons begin to fire in response to low-threshold afferent 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 significantly 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-fibers (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 fiber can produce a greater depolarization of the second-order neurons in the spinal cord. This may reflect 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 efficacy occurs selectively on spinal projection neurons (i.e., the output cells of the dorsal horn). Thus, strong activation of nociceptive sensory afferents 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- D -aspartate (NMDA) subtype of glutamate receptor is necessary to induce long-term potentiation (LTP) at nociceptive synapses in the superficial 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 confirmed that both NMDA and NK1 receptors are involved in the induction and maintenance of the central sensitization produced by high-threshold nociceptive afferent inputs at the behavioral level. Because central sensitization is likely to contribute to the postinjury pain hypersensitivity states in humans, 18 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 reflects a loss of synaptic inhibition in the dorsal horn. This has emerged from previous experiments showing that the blockade of spinal γ-aminobutyric acid A receptor (GABA A R) and glycine receptor (GlyR) (the two major 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 A R-mediated synaptic currents in superficial dorsal horn 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 A R and GlyR reflects the influx of Cl – across the cell membrane. The magnitude (and direction) of this flow 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 A R (or GlyR), which translates into weaker synaptic inhibition.
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 afferents. This occurs in large part through the activation of inhibitory spinal interneurons by Aβ sensory fibers. However, given the previously discussed reductions in the efficacy of GABAergic and glycinergic transmission, this mechanism will be much less effective after peripheral nerve injury, allowing for greater firing 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 significant 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 afferent 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 proinflammatory 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 efficacy 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 effect was seen if the dorsolateral funiculus, the main pathway from the RVM to the dorsal horn, was lesioned prior to the nerve injury. These effects 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 reflect increased activation of “ON” cells in the RVM. As first described by Fields, 19 this subtype of neuron in the RVM increases its rate of action potential firing immediately before the tail-flick 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 firing 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 effects 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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Steven H. Horowitz

Current concepts of acute and chronic pain disorders distinguish “nociceptive,” “inflammatory,” “functional,” and “neuropathic” pains. 1 Nociceptive pain is the most common pain experienced when pain receptors (nociceptors) are activated, as in tissue injury. Inflammatory pain also involves nociceptor activation as a consequence of inflammation. 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 manner. 1 Damage to, or dysfunction of, these pain (somatosensory) pathways, peripherally or centrally, can result in a different, less frequent, but nevertheless important pain picture—that of neuropathic pain. Neuropathic pain confers no functional benefit and may be considered a “maladaptive” response of the nervous system to the primary pathology. 1
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 the nervous system.” 2 Spirited attacks arose thereafter and have continued unabated, mostly over the terms “lesion” and “dysfunction.” The definition has been considered narrow if the pain relates to a lesion and broad if it relates to dysfunction. 3 Either way, it presupposes a demonstrable abnormality exclusive to the nervous system; not the result of ongoing tissue injury elsewhere. 4 It is the word “demonstrable” that is operative in this chapter.
The definition also presupposes underlying pathophysiologic mechanisms affecting 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 have clinical relevance (with exceptions). 5 - 7 Such mechanisms include spontaneous and ectopic afferent discharges, alterations in ion channel expression, peripheral collateral sprouting of afferent neurons, sprouting of sympathetic neurons into dorsal root ganglia, nociceptor sensitization, recruitment of silent nociceptors, dorsal horn deafferentation, central sensitization with changes in receptive field properties, decreased descending inhibition, and cerebral cortical reorganization, among others. 1, 5 - 10
The disorders associated with neuropathic pain include polyneuropathies such as those secondary to diabetes mellitus, alcoholism, and amyloidosis; idiopathic small fiber 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, inflammatory, 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 pathophysiologic mechanisms. 8 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 mechanisms. 8 - 10 For these and other reasons, including the failure of etiology-based or anatomy-based classifications to be therapeutically helpful, a mechanistic approach to neuropathic pain management is currently advocated. 1 Ideally, specific mechanisms or combinations of mechanisms would relate to specific signs and symptoms (specific somatosensory phenotypes) and, ultimately, specific therapies. 11 Unfortunately, no objective methods of diagnosing underlying pain mechanisms exist at present. 12 Should such methods be developed, diseases-based symptom palliation strategies can be supplemented with “targeted” mechanism-specific pharmacologic management. 13

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 specific 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 affected 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 pains to differentiate ongoing from provoked activities. 6, 9 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 affecting sensory fibers is more likely to be painful, especially if inflammation and ischemia are prominent, as in the vasculitidies. 8 In painful polyneuropathies, for example, idiopathic small fiber neuropathy and diabetic polyneuropathy with predominant small fiber (Aδ- and C-fibers) damage, the burning, lancinating, jabbing pains with pins-and-needles 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 affect 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 flanks. In patients with painful polyneuropathies, Otto and coworkers 14 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 increases with repetitive stimulation (windup-like pain). 8, 9 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, fulfill 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 fiber neuropathies, deficits occur in thermal and pain perceptions and sometimes touch, whereas large fiber functions (e.g., muscle strength, reflexes, and perception of vibratory and proprioceptive stimuli) are normal. In combined large and smallfiber polyneuropathies, all these functions are compromised. Symmetrical distal autonomic dysfunction is often present but rarely severe.
In patients with significant neuropathic pain, clinical neurologic deficits are demonstrable in many conditions, but not in others, for example, trigeminal and glossopharyngeal neuralgias and, more than occasionally, postherpetic neuralgia. Patients with small fiber 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 suffered 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 specific 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 levels.
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 neuropathy 15 ; Postherpetic neuralgia, defined as chronic pain present 4 or more months after resolution of the acute herpes zoster (shingles) rash, occurs in 13% to 20% of shingles patients 16 ; and after direct nerve injury during phlebotomy, persistent pain is rare, perhaps present after 1:1,500,000 procedures. 17
3. The presence of pain is presumed to reflect damage to the small myelinated (Aδ-) and unmyelinated (C-) nociceptive fibers within peripheral nerves. 8 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 fibers (Aαβ-). The most significant measured parameters are maximum nerve conduction velocity (NCV), for the segment of nerve between the stimulating and the recording electrodes, and amplitude and configuration of the resulting signals—the compound motor action potential (CMAP) evoked from motor fibers and the sensory nerve action potential (SNAP) evoked from sensory fibers. 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-fiber 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 fiber dysfunction. Abnormal EMG features such as acute and chronic denervation indicate involvement of large motor nerve fibers 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 fiber neuropathies, because there is indirect electrodiagnostic evidence of progression to large fiber involvement 5 to 10 years after the onset of pain. However, some patients had preserved large fiber functions over a 10-year period. 18

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, specific fiber functions can be assessed: Aδ-fibers with cold, cold-pain, and mechanical pain detection thresholds; C-fibers with heat and heat-pain detection thresholds; and large fiber (Aαβ-) functions with vibration detection thresholds and mechanical detection thresholds to von Frey hairs. 11, 19 Elevated sensory thresholds correlate with sensory loss; lowered thresholds occur in allodynia and hyperalgesia. 19 Certain QST findings may relate to specific pathophysiologic mechanisms associated with neuropathic pain: heat hyperalgesia to peripheral sensitization and static mechanical hyperalgesia or dynamic mechanical allodynia to central sensitization. 11 In generalized polyneuropathies, when all quantitative sensory thresholds are elevated, it is inferred that all fiber types are affected, whereas if a dissociation exists wherein vibration thresholds are normal but the other thresholds are elevated, a small fiber neuropathy is suspected. In asymptomatic patients, abnormal QST thresholds suggest subclinical nerve damage.
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 significance. 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 deafferentation of spinal cord neurons (thermal and mechanical hypoesthesia without hyperalgesia or allodynia) in the other. 11
The shortcomings of QST are: (1) It has never been used to differentiate between neuropathic and nonneuropathic pains, and QST abnormalities occur in nonneuropathic pain conditions. 3 (2) Abnormal findings are not specific for peripheral nerve dysfunction; central nervous system disorders will also affect sensory thresholds. (3) Most significant, 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 intra- and 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 fibers 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 been extensively reviewed. 20, 21 A semiquantitative composite autonomic symptoms score (CASS), composed of the results of sudomotor, cardiovagal, and adrenergic testing, has been devised. 22 Pupillary, gastrointestinal, and sexual function tests are occasionally helpful.
The value of autonomic testing in a generalized neuropathic pain disorder, small fiber neuropathy with burning feet, has been demonstrated in several studies of patients with normal or only mildly abnormal electrophysiologic (NCVs/EMG) findings. 23, 24 Autonomic abnormalities were seen in greater than 90% of patients, the most useful tests being the quantitative sudomotor axon reflex test (QSART), thermoregulatory sweat test, heart rate responses to deep breathing, Valsalva ratio, and surface skin temperature. 23, 24 However, in a recent study of patients with diabetic polyneuropathy, discordance was noted between efferent C-fiber responses in sudomotor tests (QSART and sweat imprint) and primary afferent (nociceptor) C-fiber axon-reflex flare responses. These findings indicate that these two C-fiber subclasses can be differentially damaged or may have different patterns of regeneration and reinnervation. 25 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 point in time are essential for the diagnosis, 2 , pp 39–43 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 involving sweating and skin temperature. 26 However, there are patients with identical focal pain, but no clinical evidence of autonomic dysfunction. These patients do not meet the current definition of CRPS and their condition has been termed “post-traumatic neuralgia.” 27 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 fibers are labeled and can be visualized at light-microscopic magnifications. 28, 29 Intraepidermal nerve fiber (IENF) density and morphology (e.g., tortuosity, complex ramifications, clustering, and axon swellings) can be quantified 28, 29 and compared with control values. 30 A reduced IENF density is seen in idiopathic small fiber neuropathies, 31 diabetic neuropathy, and impaired glucose tolerance neuropathy, 32 each of which is associated with neuropathic pain. In one study, skin biopsy findings were found to be a more sensitive measure than QSART or QST in diagnosing neuropathy in patients with burning feet and normal NCVs. 33 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 fibers, as does a predominantly large fiber neuropathy, Friedreich’s ataxia, in which pain is unusual. 28, 29 Thus, the loss of IENFs is not specific for the presence of neuropathic pain.
A recent study suggests that the presence of large axonal swellings (>5 times the nerve fiber diameter) on an initial skin biopsy may predict progression of small fiber neuropathies, because this finding 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 needles) than with burning or “lightning” pains. 34
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. Specific serum antibody tests are valuable in painful neuropathies associated with neoplasia, celiac disease, and human immunodeficiency virus. 35 Cruccu and associates 3 also noted that nociceptive reflex 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 specific therapies are lacking, and present therapies have been developed mainly through trial and error. 36 Our current inability to make therapeutically meaningful decisions based on ancillary test data and defined 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 results. 36 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 “deafferentation pain,” was unproved. 36
2. In Fabry’s disease, in which small fibers are exclusively affected, 37 enzyme replacement therapy failed to influence IENF density, had mixed effects on cold and warm QST thresholds, and had beneficial effects on sudomotor findings. 38, 39 This occurred in the presence of clinical improvement as manifested in modest reductions in pain scores and in pain interference in daily life. 39
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 without pain.” 40 The authors conclude that IENF loss “cannot explain pain in all cases, suggesting that different mechanisms underpin the genesis of pain at various stages of neuropathy.” 40
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 so. 41
Along with the disparity in C-fiber subtype involvement in diabetic small fiber neuropathy, 25 these results indicate that the specificity 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 defined in Webster ’ s Third New International Dictionary ) to history and clinical examination.
Because of these difficulties and the lack of a diagnostic “gold standard,” 42 - 44 there has been renewed interest in patient symptoms and signs with the intent of establishing clinical parameters indicative of neuropathic pain. Several questionnaires and scales have been developed, 4, 12, 42 - 48 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 electrophysiological evidence” 12 ; “suspicion of neuropathic pain (by the referring physician)” 43 ; “pain … which could be clearly attributed to a peripheral or central nervous system injury … based on medical history, physical examination and electromyography, laboratory tests and/or imaging when indicated.” 46, 47
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 outcome variables, 43 thereby making the results self-fulfilling and logically inconsistent.
The results obviously vary from study to study, but one clear finding is that no single or group of pain descriptors was dispositive for neuropathic pain. At its best, in the Bennett and colleagues’ studies, 12, 44, 48 this approach attained 75% to 82% success in correctly classifying pain type (sensitivity and specificity), with other studies reporting less than 73% accuracy. 42, 43, 45 - 47 Even in the best-results studies, 12, 44, 48 individual descriptors thought specific for neuropathic pain (e.g., hot-burning, stabbing-shooting sensations) occurred in only 60% to 85% of definite 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 definite or possible neuropathic pain, which are different from those that are unlikely to have neuropathic pain.” 43 Also, “despite the ability of the S-LANSS to classify patients, around 20% to 25%… were incorrectly classified; 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 not identified by any existing tool that relies on assessment of clinical features.” 44
Recognizing this enigma, Attal and Bouhassira 49 and Bennett and his colleagues 48 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 100-mm 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 findings and ancillary test results in patients suspected of having neuropathic pain have suggested to Hansson 10 that: “Currently we lack operational criteria for translating clinical symptoms and signs into identified 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 mechanism-based classification 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 realizing that neuropathic pain is, itself, highly heterogeneous 46, 47 and multifactorial. Now, it may be beneficial 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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Patricia Bruckenthal

Older adults often have multiple comorbidities that affect 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 influence 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 vary depending on whether the older adults reside in a nursing home, 45% to 80% 1, 2 or are community dwelling. The range reported for community-dwelling elders is 25% to 50%. 3, 4 Pain continues to be an under-assessed and under-treated condition in this population. 5, 6
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 older adults. 7 - 9 The underlying disorders responsible for chronic low back pain (CLBP) are varied and require specific physical examination techniques. For example, of 111 older adults with CLBP, 84% reported sacroiliac joint pain, 19% reported pain consistent with fibromyalgia, 96% myofacial pain, and 48% hip pain. 10 Rheumatic diseases, characterized by inflammation, degeneration, or metabolic disorders, are the most common diseases reported by older adults residing in long-term care (LTC) facilities. 11 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 impairment. 12 Pain in the elderly has been associated with increased sleep disturbances. 13 These consequences can lead to less than optimal participation in rehabilitation efforts and decreased quality of life in general. Increased costs due to health care utilization have also been implicated as a result of unrelieved pain in the elderly. 14 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) project. 15 - 18 Included in this review are necessary elements such as nuances specific to older adults to assist the clinician in the assessment process. Techniques for assessing these age-specific elements are described later.
Self-report of pain is still considered the most reliable source for the cognitively intact and communicative older adult’s pain complaint. 19 Sensory deficits in vision, hearing, and cognition are common in this population and need to be identified prior to beginning the interview. These may affect the patient’s ability to complete the assessment process, and adjustments to accommodate for deficits need to be considered. This may become especially relevant when selecting appropriate pain assessment instruments. It also may be beneficial 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,” “hurting,” “discomfort,” 20, 21 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 specific to the geriatric population have been identified and are outlined later. Older persons are able to utilize a body pain map or diagram to indicate the location(s) of their pain. 22, 23 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 home-related 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 affect treatment decisions for pain. For example, nonsteroidal anti-inflammatory 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 pain. 24 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 effects, and response. This consists of prescribed, over-the-counter, and herbal supplements. Alcohol use should be specific 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) used.

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 specific 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 fluid reasoning, processing speed, and short-term memory, are part of the normal aging process. 25, 26 Factors other than dementia that should be considered as causative in cognitive decline include poor nutritional status, medication effect, depression, living environment, 25 and pain. 27 The Mini-Mental State Examination (MMSE) 28 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 with a higher pain intensity level in community-dwelling adults. 12 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 financial resources are important to the psychosocial assessment. These factors all influence the pain experience and how the patient in pain functions in these domains as well as responds to various treatments.
Depressive disorders are prevalent in people with chronic pain. 13, 29 - 31 Patients who are depressed may exhibit decreased energy and engagement in treatment modalities or avoidance of pleasant diversional activities. The Geriatric Depression Scale (GDS) 32 is one instrument that can be used to determine whether further evaluation for depression is indicated. This instrument is of particular benefit in residential care elders, whereas the Center for Epidemiological Studies Depression Scale (CESD) 33, 34 is more suited for community-dwelling elders. 35
Anxiety has also been closely associated with pain 36, 37 and often coexists with depression in this population. Anxiety may play a part in fear-related behavior that might inhibit participation in physical rehabilitation efforts. It may be useful for the clinician under these circumstances to evaluate this disorder in more detail. The Beck Anxiety Inventory 38 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 State-Trait Anxiety Inventory. 39 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 conventional nonspousal participant training. 40 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 effects are likely if long-term 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 received. 41
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, self-efficacy, catastrophizing, and pain-related fears. Coping and self-efficacy are discussed later.
Two simplistic models of coping have been described as active versus passive 42 - 44 and adaptive versus maladaptive coping. 45, 46 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 frequently used by a group of predominantly female older adults living in retirement facilities. 47 Prayer is often utilized by older adult women as a coping mechanism for pain. 48 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 effective coping skills. Patients with passive or maladaptive coping styles would likely benefit from psychological interventions 49 that would focus on more effective ways of coping.
Self-efficacy refers to the belief that one can control or manage certain outcomes of one’s life. 50, 51 Beliefs about the degree of control and self-efficacy in being able to manage pain have been well studied 52, 53 and are related to types of coping strategies used to manage pain. 54 Participation in cognitive-behavioral pain-coping skills interventions can increase self-efficacy beliefs and have been shown to decrease pain intensity, disability, and depression. 40, 55 - 57 Patients who are identified as having poor beliefs regarding their ability to manage pain may benefit from coping skills training aimed at increasing self-efficacy. 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 Adults

Pain 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 find 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 Hadjistavropoulos and coworkers, 18 Gibson and Weiner, 58 and Herr and Garand. 59 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 overwhelming. As a pragmatic yet comprehensive approach, Hadjistavropoulos and coworkers 18 recommended the administration of the Brief Pain Inventory (BPI) 60 and the Short-Form McGill Pain Questionnaire (SF-MPQ) 61 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, inflammation, 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 specific 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 inflammation, 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 fibromyalgia 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.
Specific examination maneuvers can offer 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 flexion, 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 flexion and may be suggestive of a cervical cord lesion. 62

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-off with the toes. The ability to rise unassisted from a seated position to standing, timed and averaged for 5 repetitions, 63 and the timed “up and go” test 64 are simple, quick measures of basic functional mobility.

When conducting a focused neurologic examination, strength, sensation, and deep tendon reflexes 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. Hyporeflexia may indicate nerve root compression whereas hyperreflexia 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 confirm 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 effectiveness of treatment, exacerbation of identified 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 affected. 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 deficits, the diagnosis of tumor may be delayed. Careful clinical evaluation and magnetic resonance imaging (MRI) are recommended for all patients presenting with trigeminal neuralgia. 65

Postherpetic Neuralgia
Postherpetic neuralgia (PHN) is a frequent complication after an outbreak of herpes zoster in the elderly. Sensory findings 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, and therefore, identification and intervention are crucial. 65

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 sensory abnormalities. 66, 67

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 essential. 68 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 office/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 effects of treatment should take place every 2 to 4 hours initially. Once every 8 hours is appropriate once the pain is well controlled. 69 Older adults may use terms other than pain, so questions that relate to discomfort and hurting may need to be asked. 20 The patient should be observed during an activity such as ambulation, transfers, or repositioning, because behavior and pain levels may not be equal during different activities. 20
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 does not indicate that pain is not present. 70 In fact, no statistically significant differences were seen between self-reported pain scores and heart rate, blood pressure, or respiratory rate in adult patients presenting to an emergency department for a variety of acute painful conditions. 71 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.
Clark and colleagues 72 conducted a qualitative study using focus groups in 12 nursing homes in Colorado. They identified 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) specific residents’ characteristics, such as attitudes or being perceived as “difficult,” made pain assessment more challenging. These findings have implications for practice. Education of staff 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 certified nursing assistants’ reports of behavioral and physical changes is essential to the process. The use of pain assessment tools appropriate for difficult 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 frequency of diagnosing pain in nursing home residents. 73
Similarly, Kaasalainen and coworkers 74 found that pain assessment was problematic in nursing homes and that appropriate pain assessment strategies were closely linked to effective 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 findings 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 Persistent Pain in Older Adults 19 and the American Medical Directors Association Chronic Pain Management in the Long Term Care Setting guidelines. 75 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 specific 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 findings includes reassessment at appropriate intervals, documentation, and communication of findings 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.


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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 most populations. 1, 2 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 reading and writing are secondary abilities. 3 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 an endotracheal tube. General principles of pain assessment and specific 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 worldwide increase in incidence from 25 million in 2000 to 114 million by 2050. 4 Dementia involves the development of multiple cognitive deficits manifested by impaired memory and involving cognitive disturbances and the loss of language, the ability to recognize or identify objects, and executive function. 5 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 burden. 6 In institutionalized older adults with dementia, pain or potentially painful conditions are common, with prevalence estimates ranging between 49% and 83%. 7, 8 One large-scale nursing home study documented that half of the residents reported having pain in the past week and a fourth experienced pain daily. 9 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, depression, and a history of a recent fall, unsteady gait, and verbally abusive behavior. 9
The severity of cognitive impairment and the progression of language deficit 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 deficit is the presenting symptom, with language impairments developing gradually over the course of the illness. 10 Typically, AD patients are fluent 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 trajectory of language impairment resembles that observed in AD. 11 By comparison, individuals with frontotemporal dementia (behavioral type) and primary progressive aphasia show earlier onset of language impairment and more rapid decline. 10 The subtype of dementia also appears to affect pain response. In frontotemporal dementia, a decrease in affective pain response has been documented that could be explained by atrophy of the prefrontal cortex. In contrast, with vascular dementia, an increase in affective response is reported that may be related to white matter lesions and deafferentiation in these patients. 12
Neuropathologic processes in dementia seriously affect 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 affective aspects are processed in the medial pain system (e.g., anterior cingulate gyrus, hippocampus). 13, 14 Noxious stimuli transmitted via the lateral pain system are interpreted in the somatosensory cortex, involving areas of the brain that are relatively unaffected by AD neuropathology. This explains the finding 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, the medial pain system is severely affected by pathologic processes in AD. 12, 15 The affective pain response (e.g., pain tolerance) was significantly increased in individuals with AD compared with those without dementia. 12 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 findings, evidence suggests that older adults with advanced dementia underreport pain compared 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 dementia. 16, 17 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 fracture received significantly less opioid analgesia than those with less or no impairment. 18, 19 In the nursing home setting, pain is documented less frequently in residents unable to communicate their pain, even though they have a similar number of painful diagnoses. 9, 20, 21 Moreover, less analgesia is prescribed and administered for cognitively impaired nursing home residents, even when the impaired residents have numbers of painful diagnoses similar to those in cognitively intact residents. 22, 23 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 effectively. The incidence of delirium in older adults ranges from 16% to 62% with hip fracture, 24 62% in the intensive care unit (ICU), 25 25% to 45% in older cancer patients, 26 and approximately 22% in nursing home residents. 27
Delirium is characterized by recent onset of fluctuating awareness and an inability to focus attention, a change in cognition (e.g., memory deficit, disorientation) or perceptual disturbance, and the presence of an underlying organic illness. 5 There are three clinical subtypes of delirium: hyperactive, hypoactive, and mixed. 28 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 and incoherent, with unpredictable shifting from subject to subject. 5 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 etiology is multifactorial. 29, 30 Inouye and Charpentier 29 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 identified (e.g., dehydration, electrolyte disturbance, polypharmacy, infection, hypoxia), delirium onset has also been linked to antecedent pain in hip fracture patients, 31 medical patients, 32 and older adults undergoing elective surgery. 33, 34 However, many of the analgesics (e.g., meperidine 31, 35 ) and other adjuvant medications used to treat pain (e.g., benzodiazepine 35 ) 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. Identification of pain in nonverbal older adults and of delirium both rely on observation of behavioral presentation. Moreover, there is considerable overlap between delirium behaviors and nonverbal pain behaviors. Liptzin and Levkoff 36 used behavioral items on the Delirium Symptom Interview 37 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 Symptoms Hyperactive
Fast or loud speech
Easy startling
Fast motor responses
Persistent thoughts Hypoactive
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 Examples Facial 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
Withdrawn 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 delirium episode. 38 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 older adults undergoing orthopedic surgery and not in those with cognitive impairments. 39
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 definitively 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 60% of all ICU days. 40 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.
Many older adults die in the ICU. 41 However, patients able to report the ICU experience in retrospect indicated that endotracheal intubation, mechanical ventilation, and the consequent inability to speak are extremely stressful events. 41 - 43 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’ experiencing spells of terror . 42
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 such as turning, positioning, drain and catheter removal, and wound care. 44 - 46 Adult patients described the experience of pain in critical illness as a constant baseline aching pain with intermittent procedure-related pain that is experienced as sharp, stinging, stabbing, shooting, and awful pain. 45 Although most studies have been conducted with younger patients, it should be assumed that nonverbal older adults also experience these sensations.
Identification 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% of older adults in the ICU. 25

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 section.

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 effect of pain on function, and collect data on which to base individual treatment plans. 6 Achievement of these goals is challenging in nonverbal older adults. Nevertheless, general principles can guide approaches to pain identification, measurement, and continuous monitoring, as well as selection of specific pain assessment strategies in nonverbal older adults.
The American Society for Pain Management Nursing (ASPMN) recently published recommendations for pain assessment in nonverbal individuals. 47 This comprehensive, hierarchical strategy includes five 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 management causes a reduction in the behavioral indicators believed to be related to pain. 47 These principles reflect 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, fidgeting, 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 impairment. 48 Research indicates that individuals with mild and moderate dementia and even some with severe dementia are able to self-report. 7, 48 - 50 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 identified to address reliability in using self-report instruments, Buffum and colleagues 51 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 modified 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 pain experience, and adaptation of tools to compensate for possible sensory impairments. 48, 52 However, despite these efforts, 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 affect cognition. When pain-associated pathologies are identified, the presence of pain may be assumed and appropriate pain intervention strategies should be implemented. Pain should be treated preemptively prior to initiation of any procedures known to cause pain. 1, 47 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 pathology in older adults are available. 6

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 Geriatrics Society (AGS) Panel on Persistent Pain in Older Persons 2 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 of behaviors included on a particular behavioral pain tool for use with older adults. 53
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 Impairment Issue Key Considerations Specific vs. subtle behaviors
• Specific behaviors are obvious and commonly observed in pain states (e.g. facial expressions, verbalizations/vocalizations, body movements) 2
• Subtle behaviors reflect change from usual individual behavioral pattern and are less obvious pain indicators (e.g., changes in interpersonal interactions, activity patterns or mental status) 2
• Subtle behaviors require interpretation and validation that pain is the etiology Direct observation vs. surrogate report
• Specific, obvious indicators may be observed directly; no prior history with the patient is required
• 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 report 84 - 87 Pain presence vs. severity
• Patient self-report and proxy report of pain severity show increasing disagreement with increasing severity of cognitive impairment 50
• Evidence documents surrogate/proxy ability to recognized pain presence but not intensity 84
• Professional caregivers tend to underestimate patient pain severity 84, 86, 88
• Family members tend to overestimate patient pain severity and level of discomfort 89
• A behavioral pain tool score is not the same as a pain intensity rating; pain behavior tool score and score on pain intensity ratings should not be compared 90 Sensitivity vs. specificity
• A comprehensive indicator set including obvious and less obvious pain behaviors increases sensitivity of behavioral tools to detect pain when present 91
• 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 detecting pain in those with less obvious pain presentation 91 Screening vs. diagnostic certainty
• Behavioral pain assessment may assist in screening for presence of pain, but does not provide diagnostic certainty regarding exact nature and cause of possible pain to guide treatment 64 - 66 68
• In situations in which uncertainty prevails, an empirical analgesic trial is warranted as a pain assessment strategy 1, 6, 47
Behavioral indicators for pain assessment must be appropriate to the patient population, setting, and type of pain problems encountered. The shorter behavioral pain tools tend to be direct observation–focused including specific behaviors that may be observed in a direct encounter by trained observers (e.g., grimacing, guarding, restlessness, moaning, fighting the ventilator). 54, 55 The patient may be observed for a specified period and activity for the presence or absence, intensity, or frequency of pain behaviors. 54, 56 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. Moreover, an absence of increased vital signs does not indicate an absence of pain. 57, 58
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 undertreatment. 18, 54, 59, 60 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 identification of subtle, less obvious changes in behavior that may indicate pain presence. In LTC, the certified nursing assistant is a key health care provider who has been shown to be effective in recognizing the presence of pain. 61, 62 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 provided preliminary support for this approach. 63 Buffum and coworkers 64 did not demonstrate significant 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) evaluating low-dose opioids in persons with dementia, Manfredi and associates 65 reported decreased agitation 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 receiving 3000 mg/day of acetaminophen, Chibnall and colleagues 66 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 developed by Kovach and colleagues, 67 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 significantly less discomfort and behavioral symptoms returning to baseline more frequently in the treatment group and has been shown to be effective in increasing recognition and treatment of pain in persons with dementia. 68 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 available tools 53, 69 - 72 have indicated that, although there are tools with potential, currently no tool has sufficiently 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 clinical settings. In an earlier comprehensive review, Herr and associates 53 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)

The Checklist of Nonverbal Pain Indicators 18, 54
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, concurrent validity was supported. 73 In another recent study in LTC, 91 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 needed.

The Doloplus 2 74
The 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 reflects 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 subscales were low. 75 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 contributing little to the tool. 76 Thus, despite evidence to support validity, 49, 75, 76 there is indication of need for a tool revision. Moreover, although clinicians report the ctool manual is clear, in clinical testing, nurses reported that the tool is difficult to score and interpret. 75, 76

The Pain Assessment Checklist for Seniors with Severe Dementia 77
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 version of the tool, interrater and intrarater reliabilities were high. 75 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 development. 75

The Pain Assessment Checklist for Seniors with Severe Dementia—Dutch-Revised 75
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, confirmatory testing in an independent sample is needed.

The Pain Assessment in Advanced Dementia Scale 78
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. Originally developed in English, the PAINAD has been translated and tested in Italian, 79 Dutch, 75 and German. 80 Although interrater 75, 78 - 80 and test-retest 75, 79, 80 reliabilities have been supported, internal consistency is only moderate, with the breathing item scoring persistently low. 75 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 PAINAD as too concise , with too few pain cues included. 75 In one study, raters did not use the breathing item in painful situations in over 80% of participants with pain. 75 In another study, nurses expressed uncertainty regarding the consolability item. 80 Thus, the limited number of items restricts the ability of the PAINAD to detect pain in persons with dementia with more subtle behavioral presentation.

Behavioral Pain Scale 81
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 France 81 and Morocco 82 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 patients, including some older patients (median age 64 yr, range 16–82). 83 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.

Critical Care Pain Observation Tool 55
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 effort 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 sufficient validity and reliability to warrant recommendation for broad adoption in clinical practice.


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American 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-of-the-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 . 2005;330:461-464.
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.

Howard S. Smith, Misha-Miroslav Backonja, Marco Pappagallo, Charles E. Argoff

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 difficulty when addressing NP.
Derasari 1 stated that the main impact of effective taxonomy is the framework for the interpretation of the differences and similarities in living organisms in light of comparative genetics, biochemistry, physiology, embryology, behavior, and etiology. Commonly accepted terminology and classifications 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 specificity of the term as proposed by the International Association for the Study of Pain (IASP) is contradictory to the preferred approach—the mechanism-based diagnosis and treatment of all painful conditions.
NP remains a significant challenge to diagnose and treat effectively. Perhaps, this is in part related to the difficulty in defining NP. The IASP defined NP as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.”
Controversy exists regarding the definition of NP and what it entails. Max 2 argued for removal of the words “or dysfunction” from the IASP definition and proposed that the definition for NP be “pain initiated or caused by a primary lesion of the nervous system.” Conversely, Jensen and coworkers 3 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, Merskey 4 noted that without the word “dysfunction” in the definition of NP, the entity of trigeminal neuralgia may require two subcategories, one neuropathic with a definable lesion and one not. In 2006, Gary Bennett suggested that given the present level of understanding, a clean separation between inflammatory pain and NP may not be realistic in many patients, and a satisfying definition of NP may not be currently possible.
A clinically acceptable definition of NP is vitally important because effective treatment of NP remains a challenge and the number of patients with NP is significant 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 revised definition and grading system for NP. 5
Treede and associates 5 proposed that NP be redefined/reworded as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” Peripheral NP and central NP are proposed to refer to lesions/disease of the peripheral nervous system (PNS) and central nervous system (CNS), respectively. 5
The NP grading system is used to decide on the level of certainty with which the presence or absence of NP can be determined in an individual patient. 5 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 “definite” 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 fulfill the criteria for any of these three levels, it is considered unlikely that this patient has NP. 5
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 system. †
3. Demonstration of the distinct neuroanatomically plausible distribution by at least one confirmatory test. ‡
4. Demonstration of the relevant lesion or disease by at least one confirmatory test. § 5
Treede and associates 5 pointed out that controversy over whether diseases such as complex regional pain syndrome I constitute NP will not be resolved by their proposed definition. However, it is conceivable that future tools/research may help sort this out. This new definition 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 significant 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.

Multiple measurement tools exist to assess the intensity of pain, however. In 1997, Galer and Jensen 6 published the NPS in efforts to assess the intensity of, specifically, NP. The NPS is essentially a measurement tool of NP severity. The NPS was designed to assess distinct pain qualities associated with NP. 6 In 2005, Jensen and colleagues 7 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 difficult at times to correctly recognize the neuropathic qualities of various painful complaints by patients. In 2007, Bennett and coworkers 8 reviewed five screening tools used to identify NP (with up to 80% sensitivity and specificity) ( Table 6–1 ). It can be appreciated that the first 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
In 2001, Bennett 9 published the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), which contains five symptom and two clinical examination items and is easy to score within clinical settings. In 2005, Bennett and associates 10 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 specificity 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 not designed as a measurement tool, Khedr and colleagues 11 showed sensitivity to treatment effects.

Douleur Neuropathique 4 Questions
In 2005, Bouhassira and coworkers 12 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, inflammatory 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% specificity when compared with clinical diagnosis in the development study. The first 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 Inventory (NPSI). In 2004, Bouhassira and associates 13 published the NPSI for the evaluation of different symptoms and dimensions of NP. The final version of the NPSI includes 10 descriptors (plus 2 temporal items) that allow discrimination and quantification of five distinct clinically relevant dimensions of NP syndromes. It has been suggested that NPSI is particularly suitable to assess treatment outcome.

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 2005;114:29–36.

Neuropathic Pain Questionnaire
In 2003, Krause and Backonja 14 published the Neuropathic Pain Questionnaire (NPQ), which consists of 12 items, including 10 related to sensations or sensory responses and 2 related to affect. 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% specificity compared with clinical diagnosis in the validation sample. Backonja and Krause 15 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”).

In 2005, Freynhagen and colleagues 16 published the screening tool referred to as painDETECT , which was developed and validated in German. painDETECT incorporated an easy-to-use, patient-based (self-report) 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 classified 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
In 2006, Portenoy 17 published the ID Pain, which consists of five 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 classifications. 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 field of neurology very well—for example, clearly distinct clinical courses have been mapped for demyelinating disorders of the PNS (e.g., inflammatory 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 perception—leading to a reaction to pain. Petersen and coworkers 18 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 influence 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 inflammatory 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 specifically 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 “allodynia network.” 19
The distinction between inflammatory 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 inflammation and inflammation may affect 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 inflammatory model) may actually be more of a “mixed picture” and the specific 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 inflammatory, and their influence on common painful disorders. CIDP, chronic inflammatory diabetic polyneuropathy; CRPS, complex regional pain syndrome; OA, osteoarthritis; PDN, painful diabetic neuropathy; PHN, postherpetic neuralgia; RA, rheumatoid arthritis.
Conventional older classifications 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.
Rasmussen and associates 20 examined whether symptoms and signs cluster in patients with increasing evidence of NP. They used three categories of NP (“definite,” “possible,” and “unlikely”) based on detailed sensory examination and found a considerable overlap of symptoms and signs between the categories, using the Short-form McGill Pain Questionnaire (SF-MPQ). 21
Distinguishing NP from nonneuropathic pain in a specific 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 inflammatory pain. Attempts to “tease out” “how much” (if any) of the pain complaint is neuropathic in nature may potentially be worthwhile because it may affect medical decision making regarding the planning of treatment strategies.
Backonja and Stacey 22 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 2004;5:491–497.
Smith and colleagues 23 sent the S-LANSS questionnaire to 6000 adults from general practices in the United Kingdom, along with chronic pain identification 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 significantly poorer scores for all interference items of the BPI than those with chronic pain (non-POPNO). 23 Mean scores from the NPS were also significantly higher for the chronic POPNO group reporting the worst health. 23 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 interference items in the BPI, indicating poorer health and greater disability. 23 This study supports the importance of identifying NP in the community and the need for multidimensional management strategies that address all aspects of health. 23
Postal surveys were carried out in large community samples from the United Kingdom 23, 24 and France 25 in attempts to gain information regarding the epidemiology of NP in the general population. Although different 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 reported in the general population, around 7% to 8%. 26 Interestingly, these population-based studies showed that the subset of respondents with NP features had several associated clinical characteristics that differed from other respondents with chronic pain, even after controlling for pain severity. These characteristics include significantly worse quality of life, greater interference from pain, and pain of longer duration. 26
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 diagnosed with NP if seen by a pain specialist in a clinic? Weingarten and coworkers 27 addressed this very question and reported on a community validation study of the S-LANSS in an issue of Pain . Weingarten and coworkers 27 mailed a short questionnaire that included questions on pain and, specifically, the S-LANSS to nearly 6000 community adults and received over 3500 replies. 10 A subsample of these respondents were invited for clinical assessment, and finally, a comparison was made between clinical assessment and responses to S-LANSS after a gap of 3 to 12 months. 26 Weingarten and coworkers 27 asked subjects only for “any pain in the last 3 months as opposed to pain lasting for more than 3 months.” 26 The prevalence of NP derived from the survey of Weingarten and coworkers 27 (8.8%) is very close to that reported by Torrance and associates. 24
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 confirmatory testing, although providing enough information to categorize NP based on the criteria of Treede and associates, 5 is not sufficient to precisely dissect all patient’s pain complaints into neuropathic, nonneuropathic, or mixed. Ideally, a valid specific 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 specific testing of the skin such as provocative or challenge testing, assessing whether various agents (e.g., capsaicin) exacerbate, alleviate, or do not affect 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 examination in the analysis of somatosensory aberrations. 28 This approach, derived from experimental psychophysics, consists of measuring the responses (i.e., nonpainful sensations and pain) evoked by mechanical and thermal stimuli, the intensity of which is controlled by automated devices. 29
QST is based on precise definition of the stimulus properties (modality, intensity, spatial, and temporal characteristics), analysis of the quality of evoked sensation, and quantification of its intensity. 29 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 suprathreshold stimuli. 30 - 32 The German Research Network on Neuropathic Pain (DFNS) developed a comprehensive QST protocol consisting of 7 tests measuring 13 parameters and defined a set of normative data for thermal and mechanical detection and pain thresholds for the hand, foot, and face in healthy volunteers. 33
The expected role of QST in the definition of a mechanisms-based approach to NP has not yet been met. QST has helped to determine selective roles for different peripheral fibers or ascending pathways in specific conditions. 34 - 36 However, there are probably no simple relationships between the pattern of sensory deficits and NP symptoms 37 ; and the ultimate aim of marrying clinical symptoms and signs with pain pathophysiology still has to be accomplished. 29
Max 38 stated that small academic clinical trials so far have failed to identify obvious differences in the response to various drugs of different pain symptoms in the same condition. In contrast, there are clear differences in the analgesic responses of patient groups distinguished on the basis of etiology or tissue origin of pain, factors that tend to be associated with groups of mechanisms. 38
An emphasis has been on supplementing a disease-based treatment approach with one based on symptoms (used as an indicator) and their underlying putative mechanisms. 39 This approach accounts for the observation that patients with one disease entity (e.g., diabetic neuropathy) may have vastly different symptoms arising from different mechanisms and that patients with different diseases may have similar symptoms arising from the same mechanism. 40
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 specifically targeting the mechanisms underlying these symptoms, an improved therapeutic response may be realized. 41 The clinician may need to explore “rational polypharmacotherapy” on a case-by-case basis when a single agent is ineffective in relieving a patient’s reported symptoms. 41

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 Assessment (MDPA) has been proposed by Backonja and Argoff. 42
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 specific 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 affect NP. Even though many comorbidities do not have direct effects on the clinical manifestations of NP, some comorbidities may indirectly affect 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 treatments. Ploghaus and coworkers, 43 through advances in neuroimaging, elegantly demonstrated a neural basis for the relationship between anxiety and pain in humans. The influence of pain on psychiatric comorbidities and vice versa are extremely complex and far from clear. The availability of many specific assessment tools for human as well as bench research provides ample opportunities to study those relationships.
Backonja and Argoff 42 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 specifically and, on the basis of that assessment, rank-ordering components that contribute to the patient’s presentation at any given time. 42 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 catastrophize.
IV. Impact of pain on ability to function (with loss of function comes the disabilities) and quality of life.
The most significant 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 specific to NP) that can be used to assess various domains of functioning in patients with persistent pain. 44 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 specific 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 Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale (all four domains being assessed by two or more different methods) 45 ( 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

Assess pain and establish the diagnosis of NP 53, 54 ; 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 2 δ ligand, either gabapentin or pregabalin.
• 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 first-line 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 treatment.
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., <30% reduction) at target dosage after an adequate trial, switch to an alternative first-line medication.

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, with no more than 40% to 60% of patients obtaining partial relief of their pain. 45
Thus, many patients may periodically suffer in silence, adjust coping strategies, become a recluse, retreat or rest, and/or resort to alternative pain-relieving efforts. Closs and associates 55 interviewed patients with persistent pain in attempts to learn about how individual sufferers manage the effects of NP. The most common management strategy was the use of conventional medications, often associated with poor effectiveness and unpleasant side effects. Complementary and alternative medicine strategies were often sought but were largely associated with suboptimal results. Many patients found resting or retreating helpful. 55 Patients exhibited a repeating cycle of attempt followed by new attempts. Some had tried to accept their pain, but there was insufficient psychological, social, emotional, and practical support to allow them to do this successfully. 55
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 specific 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.
However, even though the proposed definition and grading system of Treede and associates 5 may serve effectively 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 proposed definition and grading system of Treede and associates 5 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 confirmed 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 confirm the diagnosis of the suspected lesion or disease. These confirmatory tests depend on which lesion or disease is causing NP. 5

Daniel Ciampi de Andrade, Xavier Moisset, Didier Bouhassira

Brain functional imaging has opened up new possibilities for investigating the brain structures involved in pain perception in humans, providing the fields 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: positron-emission 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 fibromyalgia, 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 molecule with isotopes to form a complex (H 2 15 O, 18 F-deoxyglucose) should not 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 with an electron, rendering the spatial resolution of PET scans low (4 mm). 1
15 O is a commonly used isotope in studies of pain. It is combined into natural molecules, such as water, to form H 2 15 O. It is used to detect changes in regional cerebral blood flow (rCBF) as an indicator of neuronal activity. 2, 3 The results, expressed as the area “activated,” correspond to the net change in blood flow in this specific 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 final 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 interest in different sessions. 1
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, depending on the probe molecule chosen. Studies with [ 18 F] fluorodopa and opioid receptor ligands have made a major contribution to studies in the field of pain and neurology.

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 significantly changes across conditions. Deoxyhemoglobin (DeoxyHb) molecules have four unpaired electrons with paramagnetic properties, modifying the signal in T 2 -weighted images. A local increase in the ratio of oxy- to deoxyhemoglobin results in regional enhancement of the T 2 -weighted signal, indicating a net increase in local blood flow. 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 offers 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 finer 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 of stimulus induction and image acquisition. 1
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 differentiate 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 findings 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 prefrontal cortex (PFC) 1, 4 - 10 ( Fig. 7–1 ).

Figure 7–1 The physiologic pain matrix . The main regions displaying an increase in regional cerebral blood flow (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-affective 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 different structures from the physiologic pain matrix are preferentially associated with specific 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 specifically linked to the emotional-affective 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 specifically 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-affective 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 different 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 specific 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 difficult, for example, to find sufficient 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 findings 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 defined 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, frequently described as “burning,” “freezing,” or “electric shock–like.” 11 - 13

Figure 7–2 Multiple symptoms in patients with neuropathic pain . The patients may present various combinations of spontaneous and evoked pain, depending on different 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 different neuropathic symptoms may involve different mechanisms, and consequently, they may respond differently to commonly used therapeutic molecules. This finding highlights the need to tailor individual treatment regimens to the symptoms of each patient. 14 - 17 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 during spontaneous neuropathic pain. In 1988, Laterre and coworkers 18 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 finding has since been reproduced in almost all studies of spontaneous neuropathic pain. 19 - 21 However, the patients included in these studies were highly heterogeneous. In some studies, it was not entirely clear whether the patients suffered true neuropathic pain. 20 In others, the presence of continuous, spontaneous pain during the scan was not fully assessed. 18 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 conflicts with data for microelectrode recordings from the thalamus of patients with chronic pain undergoing stereotaxic surgery or from animal studies. 22, 23 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 deafferentation due to chronic neuropathic lesions, but this cannot account for the surprising increase in thalamic signal after analgesic procedures, such as cordotomy. 18 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 different 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 homologous contralateral side and rest conditions 24 - 30 (see Fig. 7-3B ). In contrast, most studies have reported an absence of activation of the ACC and IC. 25, 29, 31 These findings 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 pain. 4 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 and brainstem, as highlighted by the role of this structure in the placebo effect. 32
Similar results have been reported in studies based on an experimental model of mechanical allodynia induced by intradermal or topical applications of capsaicin in normal individuals. 33 - 36 In particular, despite the obvious differences 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 allodynia. 27 - 29 The only direct comparison of brain activation associated with cold and dynamic allodynia in a small group of patients with syringomyelia suggested that these two subtypes of allodynia induced distinct changes in brain activity. 29 However, further studies with a larger number of patients are required to determine whether this difference reflects true differences in the mechanisms of these two types of allodynia.

CRPS I (formerly known as sympathetic reflex 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 lateral (S1, S2) and medial (insula, ACC, PFC) pain systems. 37 - 39 The presence of ACC activation reported in most studies contrasts with the findings obtained for mechanical allodynia associated with well-defined neuropathic pain. This highlights the difficulty 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 different regions of the ACC have different 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 allodynic pain in CRPS I patients. 37 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 different 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 sympathetic block (SB). 40 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 procedure.
Cortical reorganization, which is characterized by a reduction in the BOLD signal in S1 and S2 during nonpainful tactile stimulation of the affected 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 affected limb. 41

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. Effective coping strategies in these patients have been proposed to explain these surprising observations. 42, 43 However, conflicting results were reported in a more recent study from the same group 44 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 conflicting results may be accounted for by the small number of patients (six) evaluated in the first study. 43
Low back pain (LBP) is a highly prevalent condition and is the second most frequent symptom-related reason for which patients consult a physician. 45 It is frequently classified 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 differential pattern of activation during two different components of spontaneous pain in LBP patients: “increasing” and “high constant" pain. 46 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 density in the same area of the dorsolateral PFC (DLPF) in LBP patients. 47
In LBP patients, the application of a painful heat stimulus to the lower back induced a significantly stronger bilateral signal in the IC, S2, and ACC and a significantly stronger signal in the right DLPF than that observed in normal controls.
Other studies have evaluated brain processing in LBP patients during experimental pain distant from the lower back region. Derbyshire and colleagues 48 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 fibromyalgia) and controls, but the intensity of the signals was greater in patients. 49
These studies in patients with RA and LBP tend to confirm that the changes in brain activity associated with clinical nociceptive pain are different, at least quantitatively, from those induced by experimental pain. In particular, chronic clinical nociceptive/inflammatory pain seems to be more specifically 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 specific 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 different types of pain (e.g., neuropathic, nociceptive) and probably different pain symptoms (spontaneous continuous pain, allodynia) involve different brain mechanisms. These findings highlight the need for a more rational and pathophysiologic classification of pain syndromes. Future studies should also help to define the place of functional neuroimaging in mechanism-based approaches to chronic pain.


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Howard S. Smith, Kenneth L. Kirsh

The field 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 affects 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 effectiveness 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 office 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 specific 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 effects, and (4) drug-related behaviors. These domains have been labeled the “Four A’s” (Analgesia, Activities of daily living, Adverse effects, and Aberrant drug-related behaviors) for teaching purposes. There are, of course, many different 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 field 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 effects, 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 effects 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 effects (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 filled 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 off” the opioids because of adverse effects, even if they perceived that opioids were providing reasonable analgesic effects. The distress that may be caused by opioid adverse effects may also be seen in acute postoperative pain patients, who may occasionally ask to stop their opioids (despite the perception that these are effective analgesics) because of the significant distress and suffering that they believe they are experiencing from an opioid adverse effect. Therefore, it appears crucial to assess opioid adverse effects. 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 Effect (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 affect various therapeutic decisions. Although most clinicians probably routinely assess adverse effects of treatments, it is sometimes difficult to find 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 efficacy. Clinicians should attempt to assess multiple domains (preferably with multidimensional tools) in efforts 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 specifically 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 modified 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 significant 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, significant 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 significant other cannot describe (and the clinician cannot elicit) any significant “translational analgesia.” A patient with chronic pain who demonstrates a failure to “get off 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 off opioids. Furthermore, more evidence regarding the hyperalgesic actions of opioids in certain circumstances is mounting.
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 fill 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 specific 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 specific 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 reflect 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 difference 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. Specifically, they include the need to demonstrate that the clinician has routinely evaluated the efficacy 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 specific 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 reflect 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, significant 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 offer mechanisms for documenting the types of practice standards that those in the regulatory and law enforcement communities seek to ensure.


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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 activities.

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 periods.

8. Over the past month, my pain treatment has improved my ability to go up stairs and/or move or lift objects.

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—specific 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 activities.

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 periods.

8. Over the past month, my pain treatment has improved my ability to go up stairs, and/or move or lift objects.

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 Form

Scott S. Reuben

The primary goal of postoperative pain relief is to provide subjective comfort, inhibit trauma-induced afferent pain transmission, and blunt the autonomic and somatic reflex 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 effects should improve overall postoperative outcome. Despite our increased knowledge of the pathophysiology and pharmacology of nociception since the late 1990s, acute postoperative pain still remains a major problem. 1 Patients continue to report that their primary concern before surgery is the severity of postoperative pain. 1, 2 This is justified, because one survey revealed that 31% of patients suffered from severe or extreme pain and another 47% from moderate pain. 1
Unrelieved postoperative pain may not only result in suffering and discomfort but also lead to multiple physiologic and psychological consequences, which can contribute to adverse perioperative outcomes. 3 This can potentially contribute to a higher incidence of myocardial ischemia, impaired wound healing, 4, 5 and delayed gastrointestinal motility, resulting in prolonged postoperative ileus. 6 Further, unrelieved acute pain leads to poor respiratory effort and splinting that can result in atelectasis, hypercarbia, and hypoxemia, contributing to a higher incidence of postoperative pneumonia. 3 In addition, acute pain causes psychological distress and anxiety, leading to sleeplessness and helplessness, impairing postoperative rehabilitation, and potentially causing long-term psychological consequences. 7 Finally, it has been recognized that unrelieved acute pain may contribute to a higher incidence of chronic postsurgical pain. 8 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 afferent peripheral terminals, is a result of inflammation at the site of surgical trauma. 9 Central sensitization , an activity-dependent increase in the excitability of spinal neurons, is a result of persistent exposure to nociceptive afferent input from the peripheral neurons. 10 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 hyperalgesia) 11 ( Fig. 9–1 ).

Figure 9–1 Surgical trauma leads to the release of inflammatory 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 afferent 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 afferent 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 afferent 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 proinflammatory cytokine interleukin-1β (IL-1β) is up-regulated at the site of inflammation and plays a major role in inducing cyclooxygenase-2 (COX-2) in local inflammatory cells by activating the transcription factor nuclear factor κB (NF-kB). 12 IL-1β is also responsible for the induction of COX-2 in the central nervous system (CNS) in response to peripheral inflammation. Interestingly, it is not the consequence either of neural activity arising from the sensory fibers innervating the inflamed tissue or of systemic IL-lβ in the plasma. Instead, peripheral inflammation 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 the CNS. 13 - 15 Thus, there appear to be two forms of input from peripheral inflamed tissue to the CNS. The first is mediated by electrical activity in sensitized nerve fibers innervating the inflamed area, which signals the location of the inflamed tissue as well as the onset, duration, and nature of any stimuli applied to this tissue. 16 This input is sensitive to peripherally acting COX-2 inhibitors and to neural blockade with local anesthetics, as with epidural or spinal anesthesia. 17 The second is a humoral signal originating from the inflamed tissue, which acts to produce a widespread induction of COX-2 in the CNS. This input is not affected by regional anesthesia 13, 14 and will be blocked only by centrally acting COX-2 inhibitors. 14, 17, 18 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 response. 14, 17, 18 Therefore, the permeability of the blood-brain barrier to currently used nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors becomes important. 19

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 “fifth vital sign.” 20 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 health care system. 20 However, the increased efforts aimed at reducing patients’ postoperative pain scores may have further increased the risk of adverse effects when health care providers attempted to achieve sufficient analgesia by opioids alone. 21 - 23
The concept of multimodal analgesia was introduced in the late 1990s as a technique to improve analgesia and reduce the incidence of opioid-related adverse events. 24 The rationale for this strategy is the achievement of sufficient analgesia through the additive or synergistic effects between different analgesics. This allows for a reduction in the doses of these drugs and, thus, a lower incidence of adverse effects. Currently, the American Society of Anesthesiologists Task Force on Acute Pain Management 25 and the Agency for Health Care Policy and Research 26 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 specifically state “unless contraindicated, all patients should receive around-the-clock regimen of NSAIDs, coxibs, or acetaminophen.” 25

Currently, the administration of NSAIDs is one of the most common nonopioid analgesic techniques utilized for the management of postoperative pain. 27 NSAIDs are useful as the sole analgesic after minor surgical procedures. 28 Because of their ceiling effect for analgesia, 29 NSAIDs alone provide insufficient analgesia after major surgery, but they demonstrate a significant opioid-sparing effect. 30 The use of NSAIDs has become increasingly popular because of the concern over opioid-related side effects, 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 function. 31 In addition, unlike opioids (which are effective for reducing spontaneous pain at rest), NSAIDs demonstrate comparable efficacy for pain both at rest and with movement, 32 the latter of which may be more important for causing postoperative physiologic impairment. 33 For these reasons, it is recommended that unless contraindicated, nonselective NSAIDs should be considered the drugs of choice for the management of mild to moderate postoperative pain. 26
Nonselective NSAIDs encompass a chemically diverse group of compounds including salicylates, proprionic acids, pyrazoles, acetic acids, oxicams, fenamates, and naphthyl-alkanones 34 ( Table 9–1 ). These NSAIDs have been reported efficacious in the management of postoperative pain after dental, orthopedic, thoracic, abdominal, and gynecologic surgeries. 31, 35 Although all NSAIDs inhibit the COX enzyme, differences 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 efficacies of NSAIDs for postoperative pain. The Oxford League Table of analgesics 36 may be used to indirectly compare the efficacy of these NSAIDs against each other. This Table is based on using comparisons of different 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 efficacy 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 over a 4- to 6-hour treatment period. 37 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 efficacy of analgesics because these NNT comparisons are treatment-specific and are compared with placebo. NSAIDs do extremely well in the single-dose postoperative comparison, with NNT values ranging between 1.6 and 3.4. 36 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 20 mg, and 3.4 for intramuscular ketorolac 30 mg. 36 At these doses, the majority of NSAIDs are more effective 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 3.8 and 4.0, respectively. 36, 38
Table 9–1 Nonsteroidal Anti-inflammatory Drugs Generic Drug Name Trade Name p -Aminophenol Derivatives Acetaminophen Tylenol Salicylates
Choline magnesium trisalicylate
Trisalicylate, Trilisate
Mono-Gesic Proprionic Acids
Motrin, Advil, Nuprin
Naprosyn, Anaprox, Alleve
Ansaid Pyrazoles Phenylbutazone Butazolidin Acetic Acids
Voltaren, Cataflam
Toradol Oxicams
Mobic Fenamates
Meclofenamic acid
Ponstel Naphthyl-alkanone Nabumetone Relafen

Table 9–2 Oxford League Table of Analgesics in Acute Pain

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

Aspirin has been known to be an effective 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 doses. 53 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 first-pass effect, which occurs in the wall of the small intestine and the liver. The metabolic pathways follow first-order and zero-order kinetics. 53 A quantitative systematic review of 72 randomized single-dose trials with 3253 patients given aspirin revealed a significant analgesic effect versus that of placebo. 38 Aspirin demonstrated a clear dose-response for pain relief, even though these were single-dose studies. Significant benefit of aspirin over placebo was shown for aspirin 600/650 mg, 1000 mg, and 1200 mg, with NNT for at least 50% pain relief of 4.4, 4.0, and 2.4, respectively. 38 No apparent ceiling effect for analgesia was observed in this dose range. A comparison of the analgesic efficacy of aspirin with acetaminophen has revealed that these two drugs result in similar postoperative pain relief. 38 These results are similar to those of a previous study demonstrating that aspirin and acetaminophen are equianalgesic and, milligram per milligram, equipotent in a variety of pain models. 54 Although it possesses similar analgesic efficacy to that of acetaminophen, the use of aspirin as a postoperative analgesic has been limited by its greater side effect profile. Unlike acetaminophen, the administration of aspirin causes a significant inhibitory effect on platelet function, 55 resulting in greater perioperative blood loss. 56 Aspirin, which irreversibly acetylates the COX enzyme, causes inhibition of platelet aggregation for the lifespan of the platelet, which is 10 to 14 days. 55 In contrast, nonselective NSAIDs reversibly inhibit the COX enzyme, causing a transient reduction in the formation of thromboxane A 2 (TXA 2 ) and inhibition of platelet activation, which resolves after most of the drug is eliminated. 55 In addition, even single doses of aspirin were associated with significantly more drowsiness and gastric irritation than placebo, with numbers-needed-to-harm of 28 and 38, respectively. 38 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 excreted via the kidney. 57 The analgesic effect occurs within 30 minutes, with maximum effect between 1 and 2 hours and duration of 4 to 6 hours. 57 Ketorolac demonstrates analgesia well beyond its anti-inflammatory properties, which are between those of indomethacin and naproxen; but ketorolac can provide analgesia 50 times that of naproxen. 57 Ketorolac has antipyretic effects 20 times that of aspirin and, thus, can mask a febrile response when administered during the postoperative period. Premarketing clinical studies have demonstrated efficacy 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 treatment of moderate postoperative pain. 58 However, some studies have revealed that ketorolac is ineffective as the sole postoperative analgesic in the management of moderate to severe postoperative pain. 59, 60 Similar to other NSAIDs, ketorolac demonstrates an analgesic ceiling effect. 29 Therefore, its efficacy as an analgesic monotherapy is usually insufficient 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, ketorolac demonstrated an opioid-sparing effect of a mean of 36%. 58 Despite this reduction in opioid use, the administration of ketorolac was not associated with a concomitant reduction in opioid side effects (e.g., nausea, vomiting, pruritus, urinary retention). 58
Oral ketorolac was approved for use in the United States approximately 3 years after the parenteral form and has an efficacy similar to that of naproxen and ibuprofen. 61 The recommended maximum total daily dose of oral ketorolac is 40 mg, and it is indicated only as a continuation of the parenteral therapy. 62 The combined duration of use is not to exceed 5 days because of the increased risk of serious adverse events. 62 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 site bleeding. 63 In the first 3 years after ketorolac was approved in the United States (in 1990), 97 fatalities were reported. 64 As a consequence, the drug’s license was suspended in Germany and France. 65 In a response to these adverse events, the drug’s manufacturer recommended reducing the dose of ketorolac from 150 to 120 mg per day. 62 The European Committee for Proprietary Medicinal Products recommended a further maximal daily dose reduction to 60 mg for the elderly and 90 mg for the nonelderly. 66 Currently, there is consensus that the maximum daily dose should be as low as 30 to 40 mg. 29, 67 Further, ketorolac is contraindicated as a preemptive analgesic before any major surgery and is contraindicated intraoperatively when hemostasis is critical because of the increased risk of bleeding. 62

COX-2–Specific Inhibitors (Coxibs)
Celecoxib was the first COX-2–specific inhibitor (coxib) approved by the FDA in December 1998, followed by rofecoxib in May 1999, and then valdecoxib in November 2001. 68 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 efficacy of coxibs for the management of postoperative pain after dental, orthopedic, thoracic, gynecologic, and otolaryngologic surgeries. 69 - 75 A systematic review of COX-2 inhibitors compared with traditional NSAIDs concluded that these two classes of NSAIDs provided similar efficacy for the management of postoperative pain. 74
Although nonspecific NSAIDs are considered to play an integral role in the management of postoperative pain, 25, 26 their routine use has been limited in the perioperative setting because of concerns of platelet dysfunction, renal toxicity, and gastrointestinal toxicity. 28 Although short-term use of NSAIDs for the management of acute pain does not seem to impair renal function, 76 there are numerous reports of NSAID-induced renal failure when these drugs are utilized for the perioperative management of pain. 77 - 82 Similarly, there have been numerous reports of gastrointestinal ulceration or bleeding associated with brief exposure to NSAIDs for the perioperative management of pain. 83 - 87 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 procedures. 99 - 101 Because these major side effects are related to the inhibition of the COX-1 enzyme, the perioperative use of coxibs appears to be a safer alternative to traditional NSAIDs for the perioperative management of pain. 74, 102 The specificity of COX-2–selective inhibitors accounts for their safer gastrointestinal profile 103 and lack of antiplatelet activity 55, 68 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 were instructed to discontinue their use of NSAIDs 7 to 10 days prior to surgery. 104 Continuing conventional NSAIDs before total joint arthroplasty has been associated with a twofold increase in the incidence of perioperative bleeding, resulting in higher transfusion requirements. 90 The use of NSAIDs has been associated with other postoperative complications, including wound hematoma, upper gastrointestinal tract bleeding, and hypotension. 89 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 without such usage. 89 We have observed that discontinuing NSAIDs before total joint arthroplasty results in an arthritic flare, not only in the operative joint but also in other arthritic joints, leading to increased preoperative pain. 104 Increased pain before total joint arthroplasty is the leading cause for increased postoperative pain, prolonged hospital admission, and impaired rehabilitation. 105 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 bleeding. 104, 106
The use of traditional NSAIDs for tonsillectomy is also associated with an increased risk for perioperative bleeding and reoperation for bleeding. 101 A meta-analysis of randomized, controlled trials involving the effects of NSAIDs on bleeding after tonsillectomy concluded that “the use of NSAID therapy after tonsillectomy should be abandoned both at the hospital and at home.” 101 However, these authors did not account for the use of coxibs in their meta-analysis. A subsequent study evaluated the safety and efficacy of administering rofecoxib 1 mg/kg prior to pediatric tonsillectomy. 107 This study revealed a significant 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 data support previous findings that coxibs do not increase perioperative blood loss 68 - 75 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 efficacy for acute postoperative pain, several meta-analyses have been performed 108 - 111 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 are similar to those reported for the traditional NSAIDs. 36 The only COX-2 inhibitor to perform less well than the other coxibs or most traditional NSAIDs was celecoxib 200 mg with an NNT of 4.5. 110 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 first 24 hours then 200 mg twice daily on subsequent days. 112 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 efficacy 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 polyps in familial adenomatous polyposis. 112 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, and the drug crosses into the central spinal fluid. 19 Celecoxib is 97% protein bound, with an apparent volume of distribution of 400 L, suggesting extensive distribution into tissues. 112 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 diflucan can increase plasma levels of celecoxib. The drug has a half-life of about 11 hours. 112 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 effect on platelet function measured by serum thromboxane production and ex vivo platelet aggregation. 113 In fact, celecoxib in doses of 1200 mg/day administered for 10 consecutive days in healthy adults demonstrated no effect on platelet aggregation or bleeding time. 113
Previous studies have shown analgesic efficacy with the perioperative administration of celecoxib 200 mg for dental, orthopedic, and otolaryngologic surgeries. 110, 114 - 117 However, these clinical investigations may have underestimated the analgesic efficacy 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 (400 L). In a dose-ranging study after otolaryngologic surgery, 118 celecoxib 400 mg was more effective than 200 mg in reducing severe postoperative pain and the need for rescue analgesic medication in the postoperative period. However, even this study was flawed because these investigators failed to administer a subsequent dose of celecoxib 200 mg within the first 24 hours postoperatively. The first clinical investigation to document the analgesic efficacy of celecoxib administered for postoperative pain management according to the current acute pain guidelines demonstrated a 31% reduction in 24-hour morphine use and a significant decrease in pain scores. 119 This represents a significant improvement in analgesic efficacy 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 of celecoxib prior to the same surgical model. 114 In addition to lower morphine use, celecoxib administration resulted in significantly 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 efficacious 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 affect the efficacy and onset of analgesia. However, one meta-analysis comparing NSAIDs administered by different routes for the management of acute and chronic pain failed to detect any difference in analgesic efficacy. 120 The intramuscular and rectal routes were associated with more local adverse effects, and the intravenous route resulted in a greater risk of postoperative bleeding. 120 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 postoperative pain as soon as patients are tolerating oral intake. 120
In an attempt to provide a peripheral analgesic effect, some investigators have utilized NSAIDs administered via either topical application or local wound infiltration for the management of acute pain. These routes provide for high concentrations of these agents at the site of the inflammatory process, with the potential for a more effective reduction of inflammation. Further, there is a potential for fewer side effects because lower doses of the drug may be used, resulting in lower plasma concentrations of the NSAID. 121 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 dose of NSAID administered orally. 122, 123 For these reasons, the topical administration of NSAIDs demonstrates a lower incidence of adverse events, including gastrointestinal toxicity, compared with the oral route. 124 A quantitative systematic review of topical NSAIDs for acute pain confirmed the benefit of this route of administration. 125 After a review of the literature, it was concluded that both the topical and the oral routes provided comparable analgesic efficacy for acute pain. Further, the topical route was associated with a low incidence of systemic adverse events that were no different from those of placebo. 125 Similarly, the local infiltration of NSAIDs into the surgical site should provide for effective analgesia with minimal side effects. NSAIDs have been administered intra-articularly for knee surgery, as components of intravenous regional anesthesia (IVRA) for hand surgery, and by wound infiltration for inguinal herniorrhaphy, mastectomy, tonsillectomy, and hand surgery. 126 A meta-analysis of local infiltration of NSAIDs revealed that there was good evidence for a clinically relevant peripheral analgesic action of intra-articular NSAIDs whereas the results of IVRA and wound infiltration with NSAIDs in postoperative pain were inconclusive. 126 Unfortunately, the incidence of systemic side effects was not evaluated in any of these clinical studies.
In addition to targeting peripheral prostaglandin synthesis with the use of local NSAID administration, alternative formulations of ketorolac have been developed as a means of blocking the up-regulation of COX-2 in the CNS after surgical trauma. Because ketorolac is unable to cross the blood-brain barrier effectively, 127 studies are under way to determine the efficacy of this drug when administered via the intranasal route. 128 Intranasal drug delivery is one of the focused delivery options for brain targeting because the brain and nose compartments are connected to each other via the olfactory route and via the peripheral circulation. 129 The administration of an intranasal formulation of ketorolac provides for rapid uptake, with significant levels of the drug measured in the cerebrospinal fluid. 128 Further, minimal gastrointestinal side effects have been reported with this route of administration. 128 Another method of targeting central prostaglandin synthesis is to administer NSAIDs via the intrathecal route. Unfortunately, the current formulation of ketorolac contains alcohol (10% wt/vol), 62 which is neurotoxic, thus precluding its use as an intrathecal analgesic. However, investigators have developed a preservative-free formulation of ketorolac, which has been safely administered to humans via the intrathecal route. 130 These data support further investigation of this NSAID when administered neuraxially for the management of acute postoperative pain.

Preemptive analgesia as a concept began over 90 years ago, when Crile 131 proposed that blocking noxious signals prior to a surgical incision may lead to some degree of CNS protection against postoperative pain, though at that time, the mechanism remained unclear. It is now recognized that nociceptor function is dynamic and may be altered after tissue injury, leading to the amplification and prolongation of postoperative pain. 132 As evidence continues to accumulate concerning the role of neuroplasticity after surgery, many researchers have focused on methods by which to not simply treat the symptoms as they occur but also to prevent central sensitization from occurring through the utilization of preemptive analgesic techniques. 11 Currently, preemptive analgesia is taken to mean that a preoperative dose of analgesic is more effective than the same dose of the same drug given postoperatively. 133 The evidence in support of preemptive analgesia has been equivocal, with one systematic review of the literature demonstrating no beneficial effect 134 whereas a more recent review 135 demonstrated an overall benefit of this concept.
The preemptive analgesic effect of NSAIDs has been previously studied after a wide variety of surgical procedures demonstrating equivocal results. 11, 134 - 136 Unfortunately, many methodological problems have been encountered in these studies. 137 Reuben and coworkers 138 were the first investigators to examine the analgesic effects of administering the same dose of NSAID either before or after arthroscopic knee surgery. The results of this study demonstrated that preoperative NSAID administration produced a significantly longer duration of postoperative analgesia, less 24-hour opioid use, and lower incidental pain scores compared with administering the same drug in the postoperative period. A review of 18 randomized, single- or double-blinded studies that used an NSAID as the target intervention revealed that only 6 studies (33%) demonstrated a preemptive analgesic effect. 136 Furthermore, the beneficial effects of preemptive NSAIDs observed in most studies were minimal. The review by Moniche and associates 134 included 20 clinical trials comparing preincisional with postincisional NSAIDs using a parallel or crossover design. The authors concluded that some aspects of postoperative pain were improved by preemptive treatment in 4 of the 20 trials. Overall, the data demonstrated preemptive NSAIDs to be of no analgesic benefit when compared with postincisional administration of these drugs. In contrast, Ong and colleagues 135 reviewed data from 16 randomized, controlled trials with preemptive NSAIDs, concluding that these drugs improved analgesic consumption and time to first analgesic request but not postoperative pain scores.
The administration of coxibs seems to possess a more favorable pharmacokinetic profile than other NSAIDs when administered orally during the preoperative period. Unlike conventional NSAIDs, coxibs may be administered without food to the fasting preoperative patient 138 and do not inhibit platelet aggregation resulting in increased perioperative blood loss. 75 Further, all coxibs have demonstrated the ability to block both peripheral and central prostaglandin synthesis. 19 A recent systematic review of preoperative COX-2–selective NSAIDs demonstrated the safety and efficacy of this class of NSAIDs for the management of postoperative pain. 75 Only three studies 139 - 141 compared the preoperative administration of coxibs with traditional NSAIDs. Heigi and coworkers 139 compared rofecoxib 50 mg with diclofenac 50 mg just before induction of anesthesia in vaginal hysterectomy or breast surgery. Rofecoxib resulted in less intraoperative blood loss, less postoperative nausea and vomiting, less antiemetic use, and greater patient satisfaction. Celik and associates 140 compared rofecoxib 50 mg with naproxen 550 mg before abdominal hysterectomy and reported no difference with regard to postoperative pain, analgesic use, or nausea and vomiting. Gopikrishna and Parmeswaran 141 compared rofecoxib 50 mg and ibuprofen 600 mg before root canal surgery and reported lower pain scores with rofecoxib at 12 and 24 hours postsurgery.
Although the concept of preemptive analgesia is controversial, 134, 135 we need to move beyond the importance of reducing only the nociceptive afferent input brought about by the surgical incision. The term preventive analgesia 142 was introduced to emphasize the fact that central neuroplasticity is induced by pre-, intra-, and postoperative nociceptive inputs. Thus, the goal of preventive analgesia is to reduce central sensitization that arises from noxious inputs occurring throughout the entire perioperative period and not just from those occurring during the surgical incision. Thus, NSAIDs should be utilized throughout the entire perioperative period until the surgical wound has healed. Effective preventive analgesic techniques utilizing NSAIDs may be useful in reducing not only acute pain but also chronic postsurgical pain and disability. 143, 144

Although NSAIDs have been shown to reduce postoperative analgesic requirements by 30% to 50% in most of the clinical trials, concern still exists regarding the real clinical benefit of NSAIDs to reduce opioid-related adverse effects, thereby hastening recovery and reducing morbidity. 3, 21 Recently, several meta-analyses 40, 145, 146 and systematic reviews 75, 147, 148 have assessed the effects of NSAIDs on opioid-related side effects. The first meta-analysis, which included seven randomized, controlled trials (491 subjects), examined the effect of acetaminophen on morphine-related adverse events. 40 The studies compared the addition of acetaminophen versus placebo to standard patient-controlled analgesia (PCA) morphine for pain control after major surgery. Although the use of acetaminophen decreased morphine use by 20% over the first 24 hours, there was no reduction in the risk of any opioid-related side effects. Although the effect of acetaminophen on postoperative pain was not quantitatively analyzed as a single-pooled estimate, the authors noted that only two of the six studies found that the use of acetaminophen improved pain scores compared with those of placebo.
The second meta-analysis, which included 22 randomized, controlled trials (2307 subjects), examined the effect of NSAIDs on morphine-related adverse events. 145 Clinical studies included the addition of an NSAID versus placebo to standard PCA morphine for postoperative pain management after a variety of surgical procedures. This study demonstrated that NSAIDs decreased the relative risk (RR) versus placebo of postoperative nausea and vomiting by 30% (RR = 0.70; 95% CI = 0.59–0.84) and of sedation by 29% (RR = 0.71; 95% CI = 0.54–0.95). However, NSAIDs did not reduce the risk of developing pruritus, urinary retention, or respiratory depression. The effects on pain were not assessed.
Another meta-analysis examined whether multimodal analgesia with acetaminophen, NSAIDs, or selective COX-2 inhibitors provided benefit when added to PCA morphine. 146 Included in this meta-analysis were 10 randomized, controlled trials that examined the addition of acetaminophen, 14 that examined the addition of COX-2 inhibitors, and 33 that assessed the addition of an NSAID to standard PCA morphine for pain control after surgery. The results suggested all of the analgesics provided an opioid-sparing effect (15%–55%); however, this decrease in opioid use did not consistently result in a decrease in side effects. The use of NSAIDs was associated with a significant decrease in the relative risks of postoperative nausea, vomiting, and sedation, similar to those observed in another meta-analysis. 145 However, the use of acetaminophen or COX-2 inhibitors did not significantly decrease the risk of opioid-related adverse events compared with placebo. NSAIDs (multiple dose and infusion only), but not acetaminophen or single-dose NSAIDs, were associated with a statistically significant decrease in pain scores. The analgesic efficacy of COX-2 inhibitors was not assessed in this meta-analysis.
Finally, three systematic reviews were conducted of the analgesic efficacy of a COX-2 inhibitor compared with placebo in addition to a standard opioid analgesic regimen for postoperative pain management. 75, 147, 148 One systematic review examined the effect of preoperative COX-2 inhibitors on postoperative outcomes in 22 randomized trials with 2246 subjects. 75 Compared with placebo, preoperative administration of a COX-2 inhibitor reduced postoperative pain and opioid use in 15 of the 20 trials; however, no significant differences were observed between placebo and COX-2 inhibitors in the overall RR or incidence of postoperative nausea and vomiting in 13 of 17 trials. A second systematic review examined the effect of coxibs versus placebo in 19 randomized, controlled trials including 26 comparisons of four COX-2 inhibitors (rofecoxib, celecoxib, parecoxib, and valdecoxib). 147 Despite a significant opioid-sparing effect averaging about 35% with coxibs, opioid-related adverse events were significantly reduced in only 4 of the 26 comparisons. Quantitative analysis of combined data revealed a reduced risk for only dizziness. A third systematic review was a meta-analysis of 9 trials (1738 subjects) that examined patients’ global evaluation of analgesia after intravenous parecoxib for postoperative pain. 148 Compared with placebo, subjects that received parecoxib, especially the 40-mg dose, had a significantly superior analgesic outcome (e.g., they more frequently rated their pain control as “good” or “excellent”). However, parecoxib did not decrease the risk of opioid-related adverse events compared with those of placebo.
On the basis of this available evidence, 40, 75, 145 - 148 it appears that the use of NSAIDs, acetaminophen, and COX-2 inhibitors results in an opioid-sparing effect after surgery. However, this decrease in opioid use does not consistently translate into a decrease in opioid-related adverse events. One criticism of these findings is that many of the studies relied exclusively on spontaneous reports of patients’ adverse events, which may be less than rates obtained through direct assessment. 149 The use of an opioid-related symptom distress scale is valuable for the evaluation of symptom frequency, severity, and distress after surgery. 150 Utilizing this scale for patients receiving COX-2 inhibitors after laparoscopic cholecystectomy, 151 it became evident that a linear relationship exists between opioid doses and clinically meaningful opioid-related adverse events. 150 Analysis of available data suggests that once a threshold morphine dose in 24 hours is reached, every 3- to 4-mg increase of morphine requirements will be associated with one more clinically meaningful opioid-related symptom. This linear correlation identifies for the first time a connection between opioid-sparing effects and reduction of adverse effects. Further, many of the studies assessing opioid-related adverse effects 40, 75, 145 - 148 used methodology that does not accurately reflect conditions in actual clinical practice. NSAIDs are more likely to be used in multiple doses (which demonstrate superior analgesia vs. placebo) 146 rather than single doses for the management of postoperative pain. In addition, a more comprehensive multimodal approach (e.g., combinations of regional analgesic techniques, other adjuvant analgesics, and opioids) is probably needed to demonstrate a reduction in opioid-related adverse events and improvement in functional outcomes.
The beneficial effects of utilizing a multimodal analgesic approach, including regional analgesia and sustained COX-2 inhibition, were demonstrated in a clinical investigation for patients undergoing major knee surgery. 106 This randomized, placebo-controlled, double-blind trial evaluated the effect of combined preoperative and 13-day course of postoperative administration of a COX-2 inhibitor on opioid consumption and outcomes after total knee arthroplasty. This study documented a reduction in epidural analgesic use, in-hospital opioid consumption, pain scores, postoperative vomiting, sleep disturbance, and increased patient satisfaction in patients administered COX-2 inhibitors compared with the results with placebo. Finally, improved knee range of motion was observed both at discharge and 1 month after surgery in the group receiving perioperative COX-2 inhibition.
The benefits of utilizing NSAIDs as a component of a preventive multimodal analgesic technique have also been demonstrated for patients undergoing anterior cruciate ligament (ACL) surgery. 143, 150 A retrospective study of 1200 patients undergoing ACL surgery examined the efficacy of administering a preventive multimodal analgesic technique ( n =500) versus a standard postoperative pain protocol ( n =700). 143, 152 Patients in the preemptive multimodal group received acetaminophen 1000 mg every 6 hours and rofecoxib 50 mg daily starting 48 hours prior to surgery. In addition, 30 minutes prior to surgery, a femoral nerve block and an intra-articular injection of bupivacaine/clonidine/morphine were performed. Postoperative analgesia included acetaminophen, rofecoxib, controlled-release oxycodone, and a cryotherapy cuff. In contrast, patients in the standard postoperative analgesic group received no preemptive analgesics prior to surgery and were administered ibuprofen and acetaminophen with oxycodone on an as-needed basis postoperatively. All patients were subsequently enrolled in a 6-month accelerated rehabilitation protocol. This study demonstrated that patients who received preemptive multimodal analgesic techniques had a reduction in the incidence of pain, opioid use, postoperative nausea and vomiting, recovery room length of stay, and unplanned admission to the hospital. In addition to an improvement in short-term outcomes, patients receiving a preventive multimodal analgesic technique had a reduction in long-term complications at 1 year after surgery. 143 Long-term complications included a lower incidence of anterior knee pain (4% vs. 14%), lower number of patients requiring repeat arthroscopy for lysis of scar tissue (2% vs. 8%), and a lower incidence of complex regional pain syndrome (1% vs. 4%) in the preventive multimodal analgesic group compared with the standard analgesic group, respectively.
NSAIDs may play a pivotal role in the prevention of chronic postsurgical pain syndromes. It has been hypothesized that because COX-2 plays an integral role in the processes of peripheral and central sensitization, 13 it is possible that early and sustained treatment with COX-2 inhibitors may thwart the progression of acute to chronic pain. 153 One study revealed that the administration of celecoxib both prior to surgical incision and continually for the first 5 postoperative days resulted in a significant reduction in both acute postoperative pain and the incidence of chronic donor site pain after spinal fusion surgery. Patients receiving celecoxib had a 74% lower risk for developing this chronic neuropathic pain syndrome. There are several potential explanations for the observed lower incidence of chronic donor site pain in patients receiving perioperative celecoxib. It has been suggested that effective treatment of acute pain, particularly when accompanied by a neuropathic element, prevents the development of chronic postsurgical pain syndromes. 154 This reduction in chronic pain may be attributed to a preemptive or preventive analgesic effect in which a reduction in spinal cord neuroplasticity derives from prompt reduction in the perioperative noxious afferent input associated with surgery. 155 It is also possible that a reduction in COX-2 expression in the CNS after surgical trauma may have contributed to a later reduction in chronic pain. It has been demonstrated that allodynia and spinal prostaglandins appear to be functionally linked in the early period after nerve injury. 156 - 158 However, several weeks after injury, this prostaglandin-dependent allodynia recedes and leaves long-term, prostaglandin-independent allodynia. 159 Thus, spinal prostaglandin synthesis may be important for the induction and initial expression but not for the maintenance of spinal cord hyperexcitability. 156, 158 Thus, although NSAIDs are ineffective in the treatment of neuropathic pain, they may be effective as a treatment strategy for preventing the pathogenesis of this chronic pain syndrome.


Allergy and Hypersensitivity
All NSAIDs, including acetylsalicylic acid, may induce two types of hypersensitivity reactions, both of which are related to the inhibition of prostaglandin synthesis. These include (1) Samter’s triad (asthma triad), in which some patients suffer from the triad of intolerance to aspirin and aspirin-like chemicals, nasal polyposis, and bronchial asthma, and (2) the syndrome of urticaria and angioedema. Approximately 10% of patients with Samter’s triad will develop angioedema and uticaria when exposed to NSAIDs.
The exact mechanism responsible for Samter’s triad is unknown, but it is widely believed the disorder is caused by an anomaly in the arachidonic cascade, which causes undue production of leukotrienes. 160 When prostaglandin production is blocked by NSAIDs like aspirin, the cascade shunts entirely to leukotrienes, producing the allergy-like effects. Leukotriene antagonists and inhibitors such as montelukast sodium (Singulair, Merck & Co., Inc., West Point, PA) show great promise in treating patients with Samter’s triad. 160 Because the intolerance reactions to aspirin and NSAIDs are caused by inhibition of the COX-1 enzyme, COX-2–selective inhibitors should be a safer alternative in the management of pain for these patients. Several studies have confirmed these findings, demonstrating that celecoxib may be administered safely to patients with a history of uticaria/angioedema, naso-ocular symptoms, bronchospasm, and/or anaphalactoid reaction induced by aspirin and/or NSAIDs. 161 - 163
In addition to these hypersensitivity reactions, patients must be asked about possible allergic reactions to sulfonamides before prescribing certain NSAIDs. The overall incidence of sulfonamide hypersensitivity in the general population is low, at approximately 3%. 164 All sulfonamides can be regarded as belonging to one of two main biochemical categories: arylamines and nonarylamines. 165 The key to a sulfonamide allergy is believed to be related to the formation of a hydroxylamine metabolite unique to the arylamine structure. Celecoxib, parecoxib, and valdecoxib belong to the nonarylamine group of medications and are contraindicated in patients allergic to sulfonamides.

The first evidence that aspirin could damage the stomach was reported in 1938 based on gastroscopic observations. 166 Subsequently, endoscopic studies have consistently demonstrated that gastric or duodenal ulcers develop in 15% to 30% of patients who regularly take nonselective NSAIDs. 167 Some of the risk factors identified for the development of NSAID-induced ulcers include advanced age, history of ulcer, concomitant use of corticosteroids, higher doses of NSAIDs (including the use of more than one NSAID), concomitant administration of anticoagulation, serious systemic disorder, cigarette smoking, consumption of alcohol, and concomitant infection with Helicobacter pylori . 168 The mechanisms by which NSAIDs cause ulceration in the stomach are by their topical irritant effect on the epithelium and their ability to suppress prostaglandin synthesis. 169 The ability of NSAIDs to cause gastric damage correlates with the duration of use, dose, and the ability to inhibit COX-1 in the gastric mucosa. 168, 170 Three studies demonstrated that some NSAIDs are associated with higher gastrointestinal risks than others. 171 - 173 In general, ibuprofen and etodolac have the lowest risk among nonselective NSAIDs; diclofenac and naproxen have intermediate risks; and piroxicam, idomethacin, and ketorolac have the greatest risk for gastrointestinal complications.
In contrast, the selective COX-2 inhibitors were found to have a significantly lower risk of gastrointestinal toxicity when compared with traditional NSAIDs, with incidences similar to those of placebo. 174 Evidence from four large-scale randomized, controlled trials showed that COX-2–selective inhibitors have reduced gastrointestinal toxicity compared with nonselective NSAIDs. 175 - 178 The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial, 175 Celecoxib Long-term Arthritis Study (CLASS), 176 Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), 177 and Successive Celecoxib Efficacy and Safety Studies (SUCCESS) 178 provided evidence that COX-2 inhibitors minimize the risk of gastrointestinal complications compared with those of traditional NSAIDs.
These findings 174 - 178 combined with the possibility that even the short-term perioperative use of NSAIDs has been associated with gastrointestinal toxicity, 83 - 87 suggest that coxibs may be safer alternatives in the management of acute pain for those patients with a past history of peptic ulcer disease or at greater risk for perforation.

Platelet activity and hemostasis depend upon a constant balance between the effects of prostaglandin I 2 (PGI 2 ) in the endothelium and those of TXA 2 in the platelets. 55 TXA 2 is converted from prostaglandin H 2 (PGH 2 ) in the platelets by the action of TXA 2 synthase, whereas PGI 2 is converted from PGH 2 in the vascular endothelium by the action of PGI 2 synthase ( Fig. 9–3 ). Furthermore, activated platelets divert some of their endoperoxides to vascular cells ("endoperoxide steal") to further provide substrate for PGI 2 formation. TXA 2 functions as a platelet activator and vasoconstrictor, whereas PGI 2 is a platelet inhibitor and vasodilator. Because platelets do not contain COX-2, all synthesis of TXA 2 in the platelet is mediated by COX-1. Therefore, therapeutic doses of highly selective COX-2 inhibitors may be advantageous in the perioperative period because there is no increased bleeding from platelet effects.

Figure 9–3 The role of cyclooxygenase (COX) in prostaglandin (PG) synthesis. Prostaglandins (PGD 2 , PGE 2 , PGF 2-α , and PGI 2 ) and thromboxanes (TXA 2 ), which are mediators of inflammation and homeostasis, are products of a biochemical cascade by which membrane phospholipids are converted to arachidonic acid, then to intermediate prostaglandins (PGG 2 and PGH 2 ) by COX, and to their final products by a series of synthases. Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce postoperative pain by suppressing COX-mediated production of PGE 2 .
Adapted from Gilron I, Milne B, Hong M. Cyclooxygenase-2 inhibitors in postoperative pain management. Anesthesiology 2003;99:1198–1208; used with permission from the American Society of Anesthesiologists, copyright 2003 by Lippincott Williams & Wilkins.

Both COX-1 and COX-2 are constitutively expressed in the human kidney. The predominant effect of COX-2 (constitutively expressed in both the cortical thick limb of the loop of Henle and the medullary interstitial cells) is in water and electrolyte homeostasis. 179 COX-1 appears to influence renal hemodynamic regulation such that inhibition of COX-1 has been shown to reduce glomerular filtration rate. 179 All NSAIDs including COX-2 inhibitors are associated with transient sodium and water retention, hypertension, and edema, all possible within the first few days of therapy. Most of these events are of minor clinical significance and resolve within 1 to 8 weeks after discontinuation of NSAID therapy. 180 Risk factors for NSAID-induced renal toxicity include chronic NSAID use, multiple NSAID use, dehydration, volume depletion, congestive heart failure, vascular disease, hyperreninemia, shock, sepsis, systemic lupus erythematosus, hepatic disease, sodium depletion, nephrotic syndrome, concomitant drug therapy (diuretics, angiotensin-converting enzyme [ACE] inhibitors, β-blockers, potassium supplements), and age 60 years or older. 180 Although short-term use of NSAIDs for the management of acute pain does not seem to impair renal function, 76 it would be sensible to delay NSAID or coxib administration in the presence of compromised renal function or perioperative dehydration, hypovolemia, and hypotension.

Bone Healing
Another concern regarding the perioperative use of NSAIDs is the possible deleterious effect on osteogenesis and spinal fusion. 181 - 184 Prostaglandins have been known for many years to have potent effects on bone metabolism, including both osteoblastic and osteoclastic activity, as well as being essential in bone repair. 185 The exact mechanism by which NSAIDs impair spinal fusion has not yet been elucidated. It has been hypothesized that the effect may be mediated by an inhibition of the inflammatory process with concomitant reduction in blood flow in the early period of osteogenesis, decreased mesenchymal cell proliferation, or inhibition of calcification of the bone matrix. 181 - 183 Many investigators recommend that NSAIDs should not be utilized in the multimodal management of acute pain for patients undergoing spinal fusion surgery. 181 - 183 Although the data are conflicting, a large body of literature derived from laboratory animal studies suggests that COX-2 inhibitors either delay or inhibit bone healing. 181 - 183 However, in these studies, NSAIDs were administered over several weeks to months at doses greater than that approved for acute pain. It has been suggested that the deleterious effects of COX-2 inhibitors on fracture healing may be reversible with short-term treatment. 186 Gerstenfeld and Einhorn 187 concluded that “management of fracture-associated pain with inhibitors of COX-2 should neither impair nor delay healing as long as the duration of treatment is consistent with current standards of care.” In addition, limiting the use of NSAIDs for short-term use, physicians should prescribe the lowest effective dose for bone surgeries. In a retrospective study of 434 consecutive patients undergoing elective decompressive posterior lumbar laminectomy with instrumented spinal fusion by a single surgeon within an 8-year period, we revealed that the short-term perioperative administration of celecoxib, rofecoxib, or low-dose ketorolac (≤110 mg/day) had no significant deleterious effect on nonunion. 188 In contrast, higher doses of ketorolac (120–240 mg/day), even when administered for less than 1 week, resulted in a significant increase in the incidence of nonunion after spinal fusion surgery. Further evidence for the safety of coxibs after spinal fusion surgery was demonstrated in a recent prospective, double-blind, randomized study in humans. 119 This was the first prospective study in humans that demonstrated that the perioperative administration of celecoxib for 5 consecutive days after spinal fusion surgery resulted in no increased incidence of nonunion at 1 year follow-up compared with placebo.
Because the short-term administration of NSAIDs appears to have no deleterious effects on spinal fusion, it is possible that denying patients these medications may pose a greater risk than nonunion. We must be cognizant of the fact that unrelieved acute pain may be associated with significant morbidity, including chronic postsurgical pain, 8 that may be reduced with perioperative coxib administration. 144

With a large surge in the clinical use of COX-2–selective inhibitors came a growing body of evidence that implicated their role (especially that of rofecoxib—currently unavailable) in contributing to an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke (first receiving a great deal of attention with the VIGOR study). 175 Although mechanisms of this risk remain uncertain, one theory holds that it relates to alteration of the PGI 2 balance favoring TXA 2 with subsequent promotion of platelet-dependent thrombosis.
In the normal state, COX-1 is the major source of PGI 2 in endothelial cells; however, COX-2 plays a significantly greater role in generating PGI 2 . Therefore, COX-2 inhibition in atherosclerosis, and thus PGI 2 generation, may have important effects on the “antithrombotic balance.” Gislason and colleagues 189 estimated that in patients with a previous myocardial infarction, the excess risk of mortality is roughly 6 deaths per 100 person-years of treatment with a COX-2 inhibitor compared with no NSAID treatment.
The Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program (consisting of the Etoricoxib Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness [EDGE], EDGE II, and MEDAL trials) evaluated the highly COX-2–selective inhibitor etoricoxib (not currently marketed in the United States) versus diclofenac (a traditional NSAID that has a bit more COX-2–inhibitory activity than COX-1–inhibitory activity) and found that both agents similarly increased the risks of thrombotic events. 190 - 193
The American Heart Association (AHA) published a scientific statement essentially stating the need to be somewhat cautious of the use of all nontraditional NSAIDs (excluding aspirin, acetaminophen, and nonacetylated salicyclates) in patients with cardiovascular disease because it is conceivable that all of these agents may be associated with some degree of increased risks of thrombotic events. 194 Furthermore, although uncertain, the AHA statement 194 hypothesized that NSAID agents with the least COX-2 inhibition and a relative preference of COX-1 inhibition (e.g., naproxen) may be associated with the “best cardiovascular risk profile,” albeit perhaps with an increase in gastrointestinal risk).


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Jennifer A. Elliott

Patient-controlled analgesia (PCA) has been in use for the management of pain since the early 1970s. This technique has historically been used in the provision of intravenous opioids for pain control. Since the late 1990s, a variety of new forms of PCA have been developed, including patient-controlled epidural analgesia (PCEA), patient-controlled regional analgesia (PCRA), patient-controlled oral and intranasal analgesia, and patient-controlled transdermal fentanyl (currently in development). Just as options for patient-controlled delivery have expanded, monitoring capabilities for the prevention of adverse events related to the use of these techniques have become more sophisticated. PCA is employed in the management of pain from a variety of conditions, including surgical pain, cancer-associated pain, and pain related to disorders such as sickle cell anemia and pancreatitis. These techniques can be used in a wide array of patients, including those at extremes of age. It is important to recognize that whereas these techniques typically allow for excellent pain control and patient satisfaction, they are not without risk. Certain patient populations—such as those with obstructive sleep apnea, chronic obstructive pulmonary disease, and renal dysfunction—may be more predisposed than others to potential adverse events with the use of PCA. Likewise, these techniques may not be appropriate for some individuals such as those with significant cognitive dysfunction. When selecting a PCA technique, the practitioner must do so with an understanding of the pharmacokinetics of the agent employed and of patient characteristics that may increase the potential for adverse events. In addition, caregivers must be alert to potential technical and programming errors that may occur and must appropriately monitor for evidence of adverse effects. PCA can be very satisfying for both patient and provider if these principles are observed.

PCA can be a highly effective means of pain reduction. Successful use of this modality depends upon proper education of both prescriber and patient. Practitioners must appropriately select dosing parameters, and patients must understand how to use the device in order to achieve desired levels of analgesia. This mode of analgesia has been used with success in a wide range of populations including those at extremes of age. 1, 2
When PCA is considered for use in a patient, it must be ascertained that the individual understands how to use the device and is physically capable of activating the demand button. Practitioners must also take into consideration some psychological factors that may influence a patient’s satisfaction with this type of analgesia. Some patients find the autonomy involved in self-directed analgesia to be comforting, whereas others may prefer nurse-delivered analgesia and may find the idea of self-delivered analgesia to be anxiety provoking. Fear of addiction or inadvertent overdosage may also cause underutilization of PCA by some individuals, which may thereby result in inadequate analgesia. 3
Traditional intermittent (as-needed) parenteral analgesia involves the administration of relatively large doses of opioid in order to achieve sustained serum opioid levels above the minimum effective analgesic concentration prior to the next dosing interval. Unfortunately, this technique results in wide fluctuations in serum opioid concentration. As a consequence of these wide swings in serum opioid concentrations after intermittent parenteral administration, patients may experience adverse effects of nausea or sedation as opioid concentrations peak and inadequate analgesia as opioid concentrations drop off prior to the next dose. PCA allows for more frequent administration of smaller analgesic doses and, thereby, may reduce the degree of fluctuation in serum opioid concentrations and attendant undesired effects. 4
Many studies have been performed to evaluate whether there are advantages to the use of PCA over those of conventional intermittent intramuscular opioid administration for postoperative pain management. 5 - 8 Several of these studies do not seem to indicate significant differences between these two modalities when assessing opioid consumption, adverse effects, or length of postoperative hospitalization. However, the vast majority do demonstrate increased patient satisfaction with use of PCA. Some studies indicate that postoperative pulmonary complications may be reduced when PCA is employed, and patient participation in postoperative rehabilitation may be enhanced as well. 9 - 11 Some drawbacks to intramuscular analgesia that have been cited include unpredictable drug absorption and pain with administration that might result in decreased usage, especially among pediatric patients. These factors may result in suboptimal postoperative analgesia. 12

PCA devices consist of a pump connected to a timer. The medication to be delivered is housed in a secure portion of the device that is accessible with the use of a key or the entry of a numerical combination on a keypad. The medication is delivered to the patient via tubing connected from the medication syringe or cartridge to an intravenous (or other applicable) catheter. The patient is able to use the device by activating a button connected to the PCA pump by a cord. Safety features incorporated into PCA devices include alarms to alert to the presence of an empty syringe, low battery, tubing occlusion, or air entrainment. The keypad used by health care professionals to program the PCA device is locked during device use to prevent dose tampering by patients or visitors. Reprogramming the device to reflect changes in the analgesic prescription typically requires use of a key or the keypad entry of a numerical combination.

When initiating PCA, the drug to be employed must be selected and several dosing parameters must be established. 13 The settings that must be chosen when starting PCA include a loading dose, a demand dose, a lock-out interval, and a bolus dose (an additional dose that can be delivered by nursing personnel if pain is uncontrolled). In addition, a continuous infusion and 1- or 4-hour maximum dose limit can be selected if desired.

Medications Used in PCA
Several opioids are currently available for use in PCA. The most commonly employed agents include morphine, fentanyl, hydromorphone, and meperidine. Methadone, oxymorphone, and alfentanil have also been administered via PCA. Factors that may influence the selection of opioid include patient disease states that might influence drug metabolism or enhance the risk for opioid-related toxicity and any history of adverse effects from prior exposure to a particular opioid. In general, meperidine is not used by most pain management practitioners for PCA owing to potential adverse effects from one of its metabolites, normeperidine, with repeated exposure to this drug. Normeperidine accumulation can result in neuroexictatory activity, including seizures. The risk of such events occurring increases when meperidine is administered in large doses (>600 mg in 24 hr) and when it is repeatedly given over a period exceeding 24 hours. The risk of toxicity from this drug is most significant among patients with renal insufficiency, and therefore, use of meperidine in this patient population is not advised.

Loading Dose
A loading dose is typically administered at the time of initiation of PCA as a means of quickly achieving a serum opioid concentration that provides effective pain control. After administration of a loading dose, patients can then self-administer additional opioid doses via the demand mode to maintain satisfactory analgesia. A loading dose should generally be prescribed when patients are experiencing significant pain upon starting PCA because use of the demand feature alone is unlikely to allow for timely establishment of sufficient analgesic serum opioid concentrations.
Loading doses can be given before PCA is initiated as multiple small opioid doses, repeated at frequent intervals until adequate analgesia is achieved (e.g., in the postanesthesia care unit [PACU]). It is vitally important to understand that PCA should be initiated only after the patient has achieved pain relief that is “in the ballpark of adequate analgesia.”

Demand Dose
The demand dose is the dose of opioid delivered each time the patient activates the PCA button, except during the established lock-out interval. The size of the demand dose selected may be influenced by factors such as age, weight (in pediatric patients), and any preexisting opioid tolerance. In general, elderly patients may respond well to lower demand doses, whereas chronic opioid users will require higher demand doses than the average adult patient. Adjustment of the demand dose may be required if evaluation of the patient’s utilization of the PCA reveals a high rate of demands.

Bolus Dose
A bolus dose is an extra dose of medication that can be delivered by nursing personnel for inadequately controlled pain. A typical scenario in which a bolus dose may need to be administered is movement-associated pain, such as when a patient participates in physical therapy. A bolus may also be necessary when a long period has elapsed between demand activations of the PCA device, as might occur with sleep. Effective bolus doses usually amount to two to three times the programmed demand dose. Bolus doses may be given as often as necessary. If frequent bolus doses are needed, adjustment of the demand dose should be considered.

Lock-out Interval
A lock-out interval is the period of time that the PCA device is unable to deliver further demand doses after activation of the demand button. This is usually set in a range of 5 to 10 minutes. Setting a lock-out interval allows the patient to appreciate the effects of the delivered opioid dose prior to administration of another dose. The lock-out serves as an integral safety feature of PCA in that it prevents rapid stacking of doses on top of one another, as might otherwise occur if dosing was achieved every time a patient attempted to activate the device. This significantly limits the potential for inadvertent drug overdosage that could result from robust attempts to achieve rapid analgesia by repeatedly activating the demand button. When assessing the patient’s pattern of analgesic use, caregivers should observe the frequency of demands the patient is attempting to obtain in addition to the actual opioid consumption. This will typically appear as “demands” or “attempts” when reviewing the PCA device history feature. If the number of “demands” or “attempts” appears high compared with the actual number of doses delivered, the patient may need to be reeducated about how PCA works, with a reminder about the lock-out interval. If both “demands” or “attempts” and actual number of opioid doses administered appear frequent, the demand dose may need to be increased to allow for enhanced analgesia.

Continuous (Basal) Infusion
A continuous (basal) infusion can be added to PCA if desired. This will be delivered regardless of patient demands. Few studies indicate a distinct advantage to the use of continuous infusions, although some believe analgesia may be better maintained with the use of basal infusions, particularly when patients are not able to activate the demand feature such as during periods of sleep. Total opioid consumption may be increased in the presence of basal infusions. There is some concern that use of continuous infusions increases the likelihood of PCA-related adverse events, with particular concern for the possibility of respiratory depression. The primary indication for use of basal opioid infusions is as a substitution for chronic baseline opioids when opioid-tolerant patients are unable to continue their regular pain medications.

One- or 4-Hour Maximum Dose
Limits can be placed on the total opioid delivered in a specified time interval. Most commonly, a 4-hour maximum dose is selected when such restrictions in dosing are desired. Setting a dose limit may be of particular importance when meperidine is employed in PCA. Owing to the potential for accumulation of normeperidine, as previously described, doses of meperidine should not exceed 600 mg in 24 hours. If dosing limits are not set, it might be fairly easy to exceed such a total daily dose with the typical dosing parameters selected for this agent when initiating PCA. Setting a 1- or 4-hour dosing limit may also provide some protection against overdosage in the event of other programming errors. However, 1- or 4-hour limits can also result in inadequate analgesia in patients requiring large amounts of opioid because restrictive limits may cause them to be “locked-out” from further doses for extended periods and can cause such individuals to be dissatisfied with their analgesic therapy ( Table 10–1 ).
Table 10–1 Current Therapy: Patient-Controlled Analgesia Setup Parameter Setting Range Loading dose *
Morphine 5–10 mg
Meperidine 100–150 mg
Fentanyl 50–100 mcg
Hydromorphone 0.5–1.0 mg Demand dose *
Morphine 1.0–1.5 mg
Meperidine 10–15 mg
Fentanyl 10–15 mcg
Hydromorphone 0.1–0.2 mg Lock-out interval 5–10 min Bolus dose 2–3 times the selected demand dose Continuous dose
This setting is not routinely used by many pain practitioners, but if a continuous infusion is desired, typical initial doses are
Morphine 1 mg/hr
Meperidine 10 mg/hr
Fentanyl 10 mcg/hr
Hydromorphone 0.1 mg/hr 1- or 4-hr maximum dose limit Setting a 4-hour dosing limit is optional with most agents, but a limit of 100 mg every 4 hr is advisable for meperidine (total daily doses should not exceed 600 mg)
* These parameters reflect average ranges for opioid-naïve patients. Opioid-tolerant patients may require larger doses, and frail or elderly patients may require smaller doses.

As with any form of medical therapy, patients receiving PCA require appropriate monitoring to ensure efficacy of treatment and to manage any possible adverse effects. 14 Assessment of the patient’s pain should be made using such tools as verbal ratings, visual analog pain scales, or the FACES pain rating scale in the pediatric setting. In conjunction with pain assessment, opioid consumption should be quantified and the PCA device history should be reviewed to evaluate how effectively the patient is using it. If it is apparent that the patient is frequently attempting to activate the demand button but the actual number of opioid doses delivered is low, patient reeducation on proper use of the device may be indicated. Conversely, if the patient has been activating the device successfully and complains of inadequate pain control despite a high rate of opioid delivery, adjustment of the demand dose may be appropriate. It is always advisable to assess patients for evidence of easily remediable sources of pain, such as a distended bladder, when contemplating whether dose increases are necessary to enhance pain control.
Patients receiving PCA must be observed for evidence of adverse effects related to their pain treatment. Vital signs with attention to respiratory rate should be monitored regularly. Oxygen saturation monitoring is often used in conjunction with PCA, although desaturation is a late indicator of adverse respiratory effects from opioid therapy. Perhaps most valuable as an early clinical indicator of opioid toxicity that could progress to respiratory depression is diminished level of consciousness. For this reason, it is important to assess patients for evidence of sedation while receiving PCA. Sedation scales are used to indicate whether patients are awake, drowsy, sleeping but easily arousable, or difficult to arouse. If a patient’s level of consciousness declines while receiving PCA, dose adjustment or termination of opioid administration may be indicated. An emerging means of surveillance for evidence of developing respiratory depression is the use of end-tidal carbon dioxide (E T CO 2 ) monitoring, which is discussed further later in this chapter. Other possible side effects of PCA that should be addressed if present include nausea, pruritus, and constipation.
Certain patient populations deserve additional mention with regards to monitoring for adverse effects when receiving PCA. Patients with various underlying organ dysfunctions may be at higher risk of toxicity related to opioid administration. Any patient with severe hepatic or renal disease may have decreased capacity to metabolize or excrete opioids and may, therefore, be susceptible to opioid accumulation with attendant toxic effects. Pulmonary reserve may be compromised in patients with chronic obstructive pulmonary disease when using PCA, and patients with obstructive sleep apnea may exhibit increased sensitivity to the sedative effects of opioids. In addition, significant hypotension can increase sensitivity to opioid effects. This may relate to decreased cerebral perfusion, resulting in increased drug effects. Decreased renal and hepatic blood flow under this circumstance may also contribute to prolongation of opioid effects. Hypotension related to hypovolemia may be exacerbated by opioid administration owing to vasodilatory effects of some opioids as well as diminished sympathetic nervous system outflow resulting from relief of pain. Vigilance should be heightened for the occurrence of adverse effects from opioid therapy in any of these patient populations ( Box 10–1 ).

Parameters that should be assessed regularly in patients receiving PCA:

Vital Signs with Particular Attention to Respirations (Breathing Rate/Depth)
Normal respiratory rates are in the range of 10–20 breaths per minute.

Visual Analog, Verbal, or FACES Pain Scores
Typically, numerical pain scores are scaled 0–10 or 0–100. Higher scores indicate increased severity of pain.

Sedation Scores
Sedation usually precedes onset of significant respiratory depression. Assessment of sedation usually involves documenting the patient’s level of consciousness via a numerical rating system such as
1 = Wide awake
2 = Drowsy
3 = Sleeping but arousable
4 = Difficult to arouse
5 = Unable to arouse

Opioid Consumption
Evaluation of medication use by the patient helps to guide adjustments in therapy. Assessment of opioid consumption allows for more accurate conversion between opioids and routes of administration. This is of particular importance in determining the needs of the opioid-tolerant patient when switching to oral medication.

Oxygen Saturation
Monitoring of oxygen saturation is not mandatory but may be useful, particularly in individuals at risk of respiratory depression with opioid therapy. Desaturation is a late indicator of respiratory depression, and thus, oxygen saturation monitoring should not be the only means used to assess for this adverse effect of opioid therapy.

End-tidal Carbon Dioxide
Adequacy of ventilation can be assessed through use of end-tidal carbon dioxide monitoring. This allows for earlier detection of respiratory depression related to opioid therapy. This type of monitoring may not yet be widely available in most institutions.

Side Effects
Common side effects of opioid therapy include nausea, sedation, pruritus, and constipation. Monitoring for these and any other adverse effects of therapy should be included in patient assessments. Treatment for any untoward effects should be provided as indicated.

There are many potential causes of PCA-related adverse events. 15, 16 Undesired effects can occur from opioid use, particularly in patients with comorbid conditions that have been described previously. Use of concomitant sedatives with PCA can result in oversedation. In addition, human error and mechanical malfunctions of the PCA device can result in adverse events. Operator errors, such as improper device setup and programming, and user-related errors, such as device tampering or PCA by proxy, are potential human errors that can result in adverse events. Mechanical failures related to defective medication syringes, electrical problems that cause inappropriate delivery of medication (either too much or too little), and failure of alarm systems may also result in adverse PCA-related events.

Operator Errors
When setting up PCA, prescribing errors such as improper dose selection and lock-out intervals may result in either inadequate analgesia or opioid-related toxicity. Patients who are opioid tolerant may experience poor analgesia if dosing parameters are restrictive, and the opioid-naïve patient may become oversedated or nauseated with overzealous dosing. When the PCA device is programmed, verification of the drug to be used, its concentration, and the dosing parameters should be performed. These settings should be reconfirmed any time changes to the prescription are made, when empty syringes are replaced, and when new personnel take over care of the patient such as at nursing shift change. Aside from programming errors, operator-related problems that may occur with PCA include incorrect loading of the medication cartridge or syringe, failure to clamp or unclamp tubing, failure to turn the machine on after syringe change, and misplacement of the key to the PCA device. Failure to plug the PCA machine into a power source can result in failure of the device once battery power is drained. This may occur when the patient is transported to and from the hospital ward for procedures or physical therapy.

Patient Errors
User related problems may occur with PCA. Some patients may not understand use of the PCA device or may confuse the demand button for the nurse call button. Patients with arthritic conditions may find it difficult to activate the demand button. Sometimes, well-intentioned friends and family members may deliver PCA by proxy. This can cause opioid toxicity, especially if the proxy continues to activate the device when the patient falls asleep or manifests sedation. There have also been cases of intentional device tampering by patients.

Mechanical Problems
Device malfunction may be caused by electrical failure or short-circuiting. In the case of electrical failure, the patient may suffer uncontrolled pain owing to interruption of drug delivery. Conversely, short-circuiting may cause delivery of medication in the absence of device activation. This could result in clinical opioid overdosage if the malfunction goes unrecognized. Siphoning of medication may occur if a defective or cracked syringe is placed in the PCA device. 17 This may also occur with inappropriate syringe seating or if the syringe is placed at a level significantly higher than the patient’s body. Other mechanical problems may relate to alarm malfunctions or defects in the tubing used to deliver the medication to the patient. Antireflux valves are typically used in the tubing for PCA to prevent medication backflow that could cause large amounts of medication to be bolused to a patient if the tubing becomes obstructed and the obstruction is suddenly relieved ( Box 10–2 ). 18, 19


Operator Errors

• Inappropriate patient selection
• Selection of inappropriate medication
• Inappropriate prescribed dosing parameters
• Insertion of wrong syringe into PCA device
• PCA pump misprogramming
• Improper loading of syringe into PCA device
• Failure to clamp or unclamp PCA tubing
• Failure to turn on PCA machine after syringe change
• PCA key displacement
• Inadequate training of staff regarding PCA and setup
• Failure to respond to device or monitor alarms

Patient Errors

• Failure to understand PCA therapy or use of device
• Confusion between PCA button and nurse call button
• Physical inability to activate demand button
• PCA by proxy
• Intentional device tampering

Mechanical Problems

• Electrical failure/battery failure
• Short circuiting of PCA device
• Siphoning of medication
• Alarm malfunctions
• Tubing defects/lack of antireflux valves
• Accumulation of drug in tubing dead space
• Hardware or software failure in PCA machine

PCA has traditionally been delivered via the intravenous route. PCEA and PCRA are other means of PCA that have more recently been developed. In addition, patient-controlled oral, intranasal, and subcutaneous analgesia have been studied with evidence of effectiveness. Currently in development is a transdermal fentanyl iontophoretic delivery system that will serve as an additional option for noninvasive on-demand analgesia.

PCEA has most extensively been studied and used in the obstetric patient, 20 likely because epidural analgesia is very commonly employed in this patient population. This form of analgesia has also been used successfully in postoperative patients, including those having undergone extensive abdominal or spinal surgery. The potential benefits of this form of PCA over conventional intravenous administration include reduction in total opioid consumption with consequent decrease in associated adverse effects. In addition, several studies suggest that use of PCEA compares favorably with use of continuous epidural analgesia, with reduction in total local anesthetic dosing and attendant motor block.

PCRA has been used for plexus analgesia as well as direct wound infiltration analgesia, as with arthroscopically guided subacromial catheter placement after decompressive shoulder surgery. 21 PCRA has been used with success in several surgical patient populations, including pediatric patients. Patient satisfaction with this technique appears to be high, and use of elastomeric infusion pumps to deliver the desired local anesthetic allows for continuation of this technique even after patient discharge to home. 22 When consideration is made to utilize PCRA at home, however, care must be taken to ensure proper instruction of the patient and caregivers, and a physician must remain readily available to address any potential problems or complications that may arise.

Noninvasive Forms of PCA
Several options for noninvasive delivery of PCA have been evaluated with evidence of efficacy. Oral PCA and patient-controlled intranasal analgesia are examples of these options. 23, 24 Modification of existing systems for intravenous PCA allow for delivery of medication by these alternate routes. When using these alternate delivery modalities, it must be taken into consideration that dose adjustment is necessary because of differences in the bioavailability of opioids when compared with intravenous administration. Once appropriate dose conversions are made, these delivery methods may provide analgesia comparable with that of intravenous PCA. These techniques are particularly useful when intravenous access is unavailable. A transdermal fentanyl PCA delivery system is currently undergoing clinical trials and is anticipated to enter the U.S. market in the near future. 25 - 28 This device is programmed to deliver 40 mcg of fentanyl via iontophoresis (through a low-intensity electrical current) when activated. The fentanyl dose is delivered over 10 minutes, and the device cannot be activated more frequently than in 10-minute intervals. The device is operable for 24 hours after the initial activation and can deliver a maximum of 80 doses. There is no basal fentanyl delivery between device activations, making it purely an on-demand system. Studies have shown use of the PCA fentanyl transdermal system to provide analgesia equivalent to that of intravenous PCA in postoperative patients. This appears to offer a promising alternative to conventional PCA because it eliminates the need for intravenous access to deliver the analgesic and it does not require as much nursing time to implement and maintain.

Some of the most recent advancements in PCA therapy involve the development of smart systems capable of adapting therapy based upon patient needs and computer-integrated systems that monitor patient ventilation and oxygenation and can terminate infusion of opioids when respiratory parameters fall outside prescribed ranges. 29 A PCA device with a computer-integrated handset has been developed that allows patients to select a pain intensity rating on a scale of 1 to 10 prior to delivering an opioid bolus. This device uses an algorithmic approach that calculates a bolus dose based upon pain intensity ratings and adjusts a basal infusion based upon demand frequency. If the patient stops making demands, the infusion is decreased and then discontinued if no further demands are made within a specified time interval. One study performed using this adapted PCA device showed that although opioid consumption was higher when using the adapted PCA compared with conventional PCA, opioid-associated adverse effects were not increased, and patient bolus requests declined as the machine varied its infusion rate based upon the patient usage patterns. 30 Similarly, a computer-integrated PCEA device that initiates a basal infusion of a local anesthetic/opioid mixture has been described. With this device, when a patient demands a PCEA bolus, the device initiates a basal infusion at 5 ml/hr of the analgesic mixture. The basal infusion is increased in 5-ml increments to a maximum of 15 ml/hr based upon the frequency of demands within the preceding hour. It subsequently will decrease the rate in 5-ml increments if no demands are made over an hour. A study using this device in laboring women showed no significant increase in the total volume of analgesic mixture used with the adapted PCEA device, but did show evidence of increased maternal satisfaction with this mode of analgesia. 31
In addition to advances in the sophistication of PCA delivery devices, monitoring capabilities for patients using these devices have also improved. One major enhancement in patient safety for those using PCA is the availability of E T CO 2 monitoring. E T CO 2 is an indicator of patient ventilatory status. Changes in ventilatory pattern typically occur long before declines in oxygen saturation, which has long been the parameter used to monitor for evidence of respiratory depression. One PCA system currently incorporates the ability to monitor both ventilation and oxygenation and thus allows for early detection of adverse respiratory effects of opioid therapy. The system alerts when respiratory parameters are out of range and does not permit delivery of any additional opioid doses. This system may be especially useful in at-risk patient populations such as those with sleep apnea and those who appear to have large opioid requirements but manifest evidence of sedation even in the presence of ongoing requests for additional analgesia. Perhaps in the future, computer-integrated systems will become available that combine the options for variable infusion based upon patient needs and the ability to monitor for evidence of adverse effects on respiratory function. This combination of features would appear to offer the optimal balance between patient satisfaction and safety.

PCA has been an important option for pain management for several decades. Intravenous PCA is widely used for a variety of painful conditions and has been especially useful in the management of acute postoperative pain. Newer PCA techniques such as PCEA, PCRA, and noninvasive forms of PCA have further expanded the options available for the treatment of pain. PCA should be undertaken with knowledge of the pharmacokinetic properties of the drugs employed and an awareness of patient factors that may increase the potential for adverse events with PCA. Practitioners and patients must be properly educated on use of PCA, and patients must be properly selected for this treatment modality. Advances in PCA technology such as variable-rate infusions that are calculated based upon patient needs for analgesia and improved patient monitoring will further enhance use of these techniques in the future.


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Melissa A. Rockford, Martin L. DeRuyter

The first description of epidural analgesia dates back to Leonard J. Corning, a neurologist, who in 1885 inadvertently injected cocaine into the epidural space of a patient. By 1900, epidural analgesia was being used to treat the pain of childbirth, and in 1931, a continuous technique was described. Considered the father of modern epidural anesthesia, A. M. Dogliotti, a 1930’s Italian surgeon, was the first to describe the “loss of resistance” technique. Phillip Bromage published the first textbook on epidural anesthesia in 1978. Bromage introduced the administration of epidural morphine for postoperative analgesia in 1980. The introduction of epidural patient-controlled analgesia with morphine followed in 1988. 1 Administration of medications into the epidural space for postoperative analgesia is a common practice today. Opioids and local anesthetics as single agents or in combination are widely prescribed, and new adjuvants and modalities of administration have been introduced. 2 The focus of this chapter is to review the favorable data supporting the application of epidural analgesia for specific surgeries, recommend dosing schemes, present a troubleshooting algorithm for inadequate analgesia, discuss recent novel approaches, and comment on adverse side effects and the American Society of Regional Anesthesia (ASRA) guidelines for management of epidurals in the setting of perioperative anticoagulation.

Epidural analgesia is produced by placing specific medications within the spinal epidural space. This space extends from the foramen magnum to the sacral hiatus. Lumbar, thoracic, and caudal levels are the most common sites used for postoperative analgesia. The epidural space is bounded anteriorly by the posterior longitudinal ligaments; posteriorly by the ligamentum flavum and vertebral laminae; and laterally by the vertebral pedicles and intervertebral foramina, through which the nerve roots exit the epidural space. The epidural space contains spinal nerve roots, fat, areolar tissue, lymph tissue, and blood vessels including a rich venous plexus. Spread of analgesia occurs in a segmental fashion both cephalad and caudad from the site of injection. Thus, the extent of spread is most affected by site of injection. Other factors that may affect spread include patient age and volume of drug. Patient height, weight, position, parturience, degree of atherosclerosis, speed of injection, and direction of the needle bevel do not seem to affect spread of epidural analgesia to a clinically significant extent.

Opioids act primarily at two sites, spinal and supraspinal. 3 Three major subtypes of opioid receptors, µ, δ, and κ, have been described. The most profound analgesic effects of opioids are mediated by µ-receptors widely distributed in both the brain (supraspinal) and the spinal cord (spinal). The δ- and κ-receptors also contribute to analgesia at the spinal level. Parenterally administered opioids primarily work at supraspinal sites, whereas opioids administered intrathecally directly communicate with the spinal cord at presynaptic and postsynaptic receptors in the substantia gelatinosa of the dorsal horn. The analgesic effect of epidurally administered opioids is primarily achieved via spinal receptor activation. The onset of epidural analgesia is typically slower than intrathecally administered drugs because the drug must first cross the dura before reaching the opioid receptors on the spinal cord. Epidural opioids also activate supraspinal opioid receptors either by vascular uptake of lipophilic agents such as fentanyl or by eventual cerebrospinal fluid (CSF) rostral migration of hydrophilic agents such as morphine.
Compared with intrathecal administration, the epidural administration of opioids has fewer side effects and fewer tendencies for respiratory depression. A significant determinant of a drug’s pharmacokinetics is its tendency to be hydrophilic or lipophilic. Consider and compare morphine (hydrophilic) and fentanyl (lipophilic). Epidural administration of morphine results in a rapid rise in plasma concentration, similar to intravenous (IV) dosing. Clinically, the analgesia associated with intravenously administered morphine may be brief, whereas epidural administration provides extended analgesia. Implied is that only a small fraction of the drug is necessary to provide spinal-mediated analgesia, which occurs as the residual morphine fraction diffuses across the dura. In comparison, fentanyl’s lipophilic properties likely account for early serum levels of the opioid after epidural administration that are significantly lower when compared with concurrent IV administration. Administration of lipophilic agents into the epidural space results in local uptake by epidural fat and other lipophilic tissues, limiting a rapid rise of serum levels. After 24 hours of continuous infusion, serum levels of IV and epidural drug approach equality as lipid deposits are saturated and drug is eluted into the circulatory system. Ginosar and coworkers hypothesized a differential site of action (spinal versus supraspinal) of fentanyl based on the method of epidural administration (i.e., bolus vs. continuous infusion). 4 They demonstrated that continuous infusion resulted in nonsegmental analgesia (suggesting opioid binding in the brain), whereas bolus administration resulted in segmental analgesia (suggesting opioid binding at the spinal cord).
Although recognizing differences in spinal versus supraspinal sites of action, selection of a lipophilic versus hydrophilic drug may likely depend on the clinical setting in which a provider practices. If continuous infusion is not available (e.g., lack of nursing supervision, lack of mechanical infusion pumps), administration of morphine may be preferred. Morphine as a hydrophilic agent remains in the CSF to a greater extent and has considerable analgesic duration. It is also associated with rostral spread, and therefore, delayed respiratory depression may occur 6 to 12 hours after dosing. Lipophilic agents such as fentanyl and sufentanil have shorter durations of analgesia, and intermittent bolusing for “spinal” analgesia would require more frequent administration. Clinically, these agents are better suited for continuous epidural infusions. Hydromorphone has a lipid solubility between those of morphine and fentanyl and can be administered either intermittently or via continuous infusion. When compared with morphine, hydromorphone has less associated pruritus and nausea. Tables 11-1 and 11-2 provide commonly administered epidural opioids, their characteristics, and dosing suggestions.

Table 11–1 Characteristics of Epidural Administered Opioids

Table 11–2 PCEA: Suggested Dosing

Postoperative epidural analgesia provided by local anesthetics produces a dermatomal distribution of paresthesia and analgesia. After administration of local anesthetic into the epidural space, the drug diffuses into the CSF at the region of the dural cuff. Locally, spinal nerve roots, dorsal root ganglia, and “rootlets” are blocked, as well as spinal nerves in the paravertebral space (which may account for a multiple-level block). Although numerous local anesthetics are applicable in producing epidural anesthesia, in considering postoperative epidural analgesia, the longer-acting amides, bupivacaine and ropivacaine, are most commonly used. Box 11–1 provides dosing regimens for continuous catheters specific for surgical site, catheter insertion site, and type of medication (opioid, local anesthetic, or both).


Thoracic, Upper Abdominal Analgesia

Thoracic Catheter
Fentanyl 5–10 mcg/ml, 30–70 mcg/hr
Hydromorphone 10 mcg/ml, 30–50 mcg/hr
Morphine sulfate 50–100 mcg/ml, 100–500 mcg/hr
Bupivacaine 0.1%, 3–8 ml/hr
Ropivacaine 0.2%, 3–8 ml/hr

Lumbar Catheter *
Fentanyl 5–10 mcg/ml, 50–100 mcg/hr
Hydromorphone 10 mcg/ml, 40–80 mcg/hr
Morphine sulfate 100 mcg/ml, 400–800 mcg/hr

Lower Abdominal, Pelvic, Urologic, Lower Extremity Analgesia

Lumbar Catheter
Fentanyl 5–10 mcg/ml, 50–100 mcg/hr
Hydromorphone 10 mcg/ml, 30–80 mcg/hr
Morphine sulfate 100 mcg/ml, 400–800 mcg/hr
Bupivacaine 0.1%, 5–10 ml/hr
Ropivacaine 0.2%, 5–10 ml/hr

* No local anesthetic recommended.

Continuous infusions have been the primary approach to postoperative epidural analgesia. Advancement in infusion pumps has allowed for patient-controlled epidural analgesia (PCEA), employing the same benefits found with IV opioid patient-controlled analgesia (IV PCA). Continuous infusions, although the mainstay, are not without management issues. Namely, failure rates for thoracic and lumbar epidurals are reportedly as high as 32% and 27%, respectively. 5 Catheter malfunction and displacement, nursing care, and attention to the infusion pump all demand utilization of limited resources. The recent introduction of liposomal morphine administered by single injection has been shown to provide significant prolonged analgesia and avoids these concerns, but it is not to be used without caution.

Epidural analgesia has earned a place among mechanisms of postoperative pain control. 6 Block and associates—in a meta-analysis of 100 controlled trials with numerous surgeries (representing thoracic, abdominal, pelvic, and lower extremities) comparing IV PCA opioids, parenteral opioids, and epidural opioids (with or without local anesthetics)—demonstrated that epidurals provided better postoperative analgesia. 7 Epidurals were also associated with lower than expected complications such as nausea, vomiting, and pruritus. Furthermore, patients receiving a combination of epidural local anesthetic and opioid as opposed to opioid alone exhibited greater improvements in analgesia.
The following sections review specific procedures and discuss data supportive for epidural analgesia. Table 11–3 provides recommended sites for catheter placement based on surgical procedure.
Table 11–3 Recommended Sites for Catheter Placement Surgical Site Catheter Site Thoracic T4–T8 Upper abdomen T6–T10 Lower abdomen/pelvis T10–L3 Lower extremity T12–L4

Thoracotomies, median sternotomy incisions, and breast surgery are commonly associated with significant postoperative pain. Benzon and colleagues, in a prospective, randomized, double-blind trial comparing thoracic epidural infusion of fentanyl to IV PCA morphine, found that patients in the epidural group reported lower pain scores, less pain associated with coughing, and less sedation. 8 Both groups shared a similar incidence of postoperative nausea and vomiting, whereas the epidural group reported more pruritus. A recent review of analgesia for thoracic surgery found that epidural analgesia had significant benefits over parenteral and IV PCA opioids. 9, 10 Median sternotomy associated with cardiac surgery is significantly painful. Wound injection of local anesthetic may provide some benefit, but administration of epidural analgesia is associated with a lower autonomic stress response, significant analgesia, and lower IV opioid requirements. 11 Segmental epidural analgesia after breast surgery provides significant patient satisfaction. In a prospective, randomized trial comparing epidural analgesia versus IV PCA, the group that received epidural analgesia demonstrated improved pain control after breast reconstruction with immediate transverse rectus abdominis musculocutaneous flap reconstruction and a shortened hospitalization. 12

Pain associated with laparotomy can be severe, and treatment with IV opioids is associated with undesirable side effects and perhaps inadequate analgesia. A 2006 Cochrane meta-analysis, representing 1224 patients undergoing abdominal aortic surgery, reviewed the efficacy of epidural analgesia versus systemic opioids. 13 The authors concluded a favorable indication for epidural analgesia. They found better pain relief (particularly with movement) up to 3 days postoperatively, a reduction in number of days requiring postoperative ventilation, and fewer cardiac, gastric, and renal complications.

The severity and acute duration of pain after certain types of abdominal, pelvic, and urologic surgery such as radical retropubic prostatectomy (RRP) make epidural analgesia an ideal form of pain control. 14 Gottschalk and coworkers performed a randomized, double-blind clinical trial of 100 patients undergoing RRP and found that preemptive epidural analgesia significantly decreased postoperative pain both during hospitalization and after hospital discharge. 15 In a recent study of 60 patients, Niiyama and associates demonstrated improved analgesia in patients undergoing lower abdominal surgery when 0.2% ropivacaine was added to epidural morphine. 16

Postoperative epidural analgesia either combined with a general anesthetic or as an extension of an intraoperative anesthetic has been employed extensively in patients undergoing lower extremity surgery, either vascular or orthopedic procedures. 17, 18 Early reports demonstrated suitable analgesia, lower incidences of reoperation, less blood loss, and lower incidence of deep vein thrombosis (DVT). 19 In a recent review of postoperative analgesia for patients after total hip arthroplasty, Fischer and Simanski recommended the use of epidural analgesia but also cautioned about an added degree of postoperative monitoring. 20

Common problems with epidural catheters include inadequate analgesia, disconnected catheters, and motor block. Testing the level of sensory block can be performed using temperature (cold/ice) or sensation (dull/sharp). Figure 11–1 provides a suggested algorithm for patients with complaint of inadequate analgesia. If the provider suspects that the epidural catheter is not functioning properly, catheter replacement should be considered. Upon inspection, the provider should remove the catheter if it has been disconnected and contaminated. If a catheter is disconnected and the fluid within the catheter has not been displaced, it is possible to reconnect the catheter using sterile technique. A bolus may be necessary after periods of disconnect. Patients who complain of an excessive motor block should be evaluated for possible subarachnoid catheter placement or supratherapeutic dosing of the epidural catheter. Once a subarachnoid block is excluded, the epidural infusion can be decreased to balance the desired level of analgesia with the acceptable degree of motor block.

Figure 11–1 Troubleshooting epidural infusions.


Extended-release epidural morphine, DepoDur (Endo Pharmaceuticals, Inc, Chadds Ford, PA), is a relatively new formulation of morphine sulfate intended to provide extended pain relief without the need for continuous infusion. The extended duration of activity results from “time-released” elution of the drug from liposomal aggregates of various sizes. DepoDur is intended for lumbar epidural administration only. It should not be mixed with any other agents, nor is injection of other agents into the epidural space recommended within 48 hours of DepoDur administration. 21, 22 Clinical trials after hip surgery, major surgery of the lower abdomen, and elective cesarean section have shown improved analgesia up to 48 hours after surgery. Side effects are similar to those of opioids administered through an epidural catheter or intravenously. Forty-eight hours of cardiopulmonary monitoring with concern for respiratory depression in the first 24 hours is recommended after drug administration. Clinical trials found that the incidence of adverse respiratory event is dose related. Respiratory depression requiring an intervention was found to occur within 16 to 24 hours of administration. The recommended lumbar epidural dose is 10 to 15 mg ( Table 11–4 ). A 20-mg dose can be considered in appropriate patients.
Table 11–4 Recommended Dosing for Depodur Type of Surgery Dose Lower abdominal surgery 10–15 mg (1.0–1.5 ml) Elective cesarean section 10 mg (1 ml) Pelvic surgery 10–15 mg (1.0–1.5 ml) Lower extremity surgery 15 mg (1.5 ml)

Clonidine is an α 2 -agonist. When administered by the epidural route, it prevents transmission of pain signals at presynaptic and postjunctional receptors in the spinal cord. Clinical studies have demonstrated sole analgesic properties as well as the ability to prolong both the sensory and the motor components of a local anesthetic epidural block. 23 Side effects of clonidine are similar when administered by epidural and IV routes. These include hypotension, decreased heart rate, dizziness, anxiety, sedation, nausea, dry mouth, confusion, and rebound hypertension. The dose for epidural clonidine ranges from 6 to 40 mcg/hr as a continuous infusion with loading doses ranging from 4 to 8 mcg/kg. A study comparing IV to PCEA clonidine as a single analgesic agent describes a PCEA bolus dose of 30 mcg every 15 minutes. 24 Gradually decreasing the dose of epidural clonidine 2 to 4 days before discontinuing therapy is recommended to prevent rebound hypertension.

It is difficult to isolate the risks and incidence of severe complications associated with epidural therapy for postoperative analgesia because they are often discussed as secondary outcomes in small trials. Common side effects of epidural analgesia are primarily a result of the specific medication administered. Table 11–5 lists some of these commonly cited side effects. A large multicentered French study, prospectively solicited from nearly 500 anesthesiologists, reported adverse events associated with regional anesthesia. 25 Included in its findings are incidences of complications associated with epidural anesthesia and analgesia for obstetric and nonobstetric patients ( Table 11–6 ). Overall, the incidence of serious complications such as epidural abscess or hematoma is quite low. 26, 27 In a 1-year national survey performed by Wang and colleagues, the estimated incidence of epidural abscess after epidural analgesia was reported to be 1 in 1930. 28 However, a similar review of approximately 50,000 epidural anesthetics did not reveal a single report of an epidural or intrathecal infection. Other reviews found the frequency of bacterial infection after neuraxial block to be as low as 1.1 per 100,000. 29 ASRA held a recent consensus conference on infectious complications associated with regional anesthesia. Upon review of the literature and expert opinion, recommendations were presented regarding aseptic technique in the placement of blocks and the management of catheters in suspicious clinical situations. These recommendations include thorough handwashing before performing procedures, removal of all jewelry, use of sterile surgical gloves, routine use of masks, and use of alcohol-based chlorhexidine solution as the antiseptic solution. 30
Table 11–5 Common Side Effects of Epidural Analgesia Opioids Local Anesthetics Nausea and vomiting Hypotension Urinary retention Motor block Pruritus Systemic toxicity Respiratory depression   Dysphoria   Sedation   Gastrointestinal dysfunction  

Table 11–6 Complications Related To Epidural Anesthesia and Analgesia

Fortunately, the risk of spinal hematoma after epidural analgesia is low. However, the increasing use and variety of anticoagulants in the perioperative setting demand an understanding and appreciation of the risk versus benefit of neuraxial analgesia in anticoagulated patients. In 2002, ASRA held its Second Consensus Conference on Neuraxial Anesthesia and Anticoagulation. 31 This is the most recent peer-reviewed consensus identifying agents of concern and formalizing a practice guideline. Table 11–7 summarizes ASRA’s recommendations.

Table 11–7 ASRA Guidelines for Regional Anesthesia in the Anticoagulated Patient
Rights were not granted to include this table in electronic media. Please refer to the printed book.
From American Society of Regional Anesthesia and Pain Medicine. Consensus Statements, Second Consensus Conference on Neuraxial Anesthesia and Anticoagulation. (accessed 1/21/2007).

For patients on chronic oral anticoagulation (warfarin), the anticoagulant therapy must be stopped (ideally 4–5 days before the planned procedure) and the prothrombin time/International Normalized Ratio (PT/INR) measured before initiation of neuraxial block. “Caution” needs to be taken when performing neuraxial techniques in patients recently discontinued from chronic warfarin therapy. Practitioners do not have a unified recommendation for the optimal INR before placing a central neuraxial needle, but ideally close to normal should be safe.
For patients receiving both low-dose warfarin (<5 mg) and continuous epidural analgesia, it is advised to monitor PT/INR on a daily basis. Before removal of the catheter, a PT/INR should be checked if warfarin has been administered for more than 36 hours postoperatively. It is allowable to remove catheters when the INR is less than 1.5. The warfarin dose should be withheld or reduced for patients with epidurals in place and an INR greater than 3.0. It is also advised to monitor routine neurologic testing of sensory and motor function during epidural analgesia infusion.
The concurrent use of medications affecting other components of clotting mechanisms (aspirin, other nonsteroidal anti-inflammatory drugs [NSAIDs], ticlopidine, clopidogrel, unfractionated heparin, and low-molecular-weight heparin [LMWH]) may increase the risk of bleeding complications without influencing the PT/INR.

Subcutaneous Heparin
Patients receiving subcutaneous heparin thromboprophylaxis do not seem to be at increased risk for epidural analgesia. The practitioner must weigh the benefits of an epidural for postoperative analgesia, and if favorable, the consensus supports that action. In cases requiring intraoperative heparin anticoagulation (e.g., heparin bolus before placement of aortic cross-clamp), a delay of at least 1 hour after epidural placement is recommended.

LMWH presents a distinct problem. There is not an accepted laboratory test to determine the extent of a patient’s anticoagulation while receiving LMWH. Monitoring of the anti-Xa level is not recommended because the anti-Xa level is not predictive of the risk of bleeding. For patients who receive perioperative LMWH, the practitioner needs to coordinate and communicate with the surgical service to optimize the time interval between neuraxial needle placement and administration of LMWH. Antiplatelet or oral anticoagulant medications administered in combination with LMWH may increase the risk of spinal hematoma, and it is best to avoid combination therapy at this time. Education of the entire patient care team is necessary to avoid such drug combinations. An alert mechanism via pharmacy or nursing must be in place to inform the anesthesia provider when patients are receiving anticoagulation. On the day of surgery, traumatic needle or catheter placement may signify an increased risk of spinal hematoma but does not necessitate postponement of surgery. However, initiation of LMWH therapy should be delayed for 24 hours postoperatively.
Patients on preoperative LMWH should be assumed to have altered coagulation status. Placement should occur at least 10 to 12 hours after the last prophylactic LMWH dose and 24 hours after the last therapeutic dose. Neuraxial techniques should be avoided in patients who received LMWH 2 hours preoperatively (peak anticoagulant activity).
Postoperative LMWH is a particular concern for practitioners administering continuous epidural analgesia. A twice-daily dosing regimen is associated with increased risk of bleeding. Therefore, indwelling catheters should be removed before initiating this LMWH thromboprophylaxis dosing regimen. Single daily dosing allows for safe maintenance of epidural catheters. Catheters should be removed a minimum of 10 to 12 hours after the last dose of LMWH. Subsequent LMWH dosing should be delayed a minimum of 2 hours after catheter removal.

Other Agents
Fondaparinux and other factor Xa inhibitors are potent agents and efficacious in DVT prophylaxis. Currently, there are little clinical data regarding risk of hematoma and neuraxial analgesia. Thus, it is recommended to avoid placement of central neuraxial needles and indwelling catheters in patients receiving these medications. Antiplatelet agents, such as the thienopyridine derivatives ticlopidine and clopidogrel, should be discontinued 14 and 7 days, respectively, before initiation of epidural analgesia. Glycoprotein IIb/IIIa inhibitors are contraindicated within 4 weeks of surgery. Epidural analgesia is contraindicated in patients receiving fibrinolytic and thrombolytic therapy. Not enough information is available on thrombin inhibitors such as desirudin, lepirudin, and argatroban to make a proper risk assessment, and it is best to avoid neuraxial analgesia in patients receiving these medications. NSAIDs, cyclooxygenase-2 inhibitors, and herbal drugs used alone do not seem to increase risk of hematoma associated with epidural analgesia.

Epidural analgesia is a well-established modality for providing postoperative pain relief. Data from individual trials, meta-analysis, expert opinion, and personal application generally support improved outcomes by numerous measures. Not all studies show a clearly demonstrable benefit. This chapter provides supportive data for specific procedures and suggestions for a dosing scheme, highlights side effects, and reinforces the concerns of perioperative anticoagulation for thromboprophlaxis in patients with indwelling central neuraxial catheters.


1. Brill S, Gurman GM, Fisher A. A history of neuraxial administration of local analgesics and opioids. Eur J Anaesthesiol . 2003;20:682-689.
2. Viscusi ER. Emerging techniques in the management of acute pain: epidural analgesia. Anesth Analg . 2005;101:S23-S29.
3. Bernards CM. Understanding the physiology and pharmacology of epidural and intrathecal opioids. Best Pract Res Clin Anesthesiol . 2002;16(4):489-505.
4. Ginosar Y, Riley ET, Angst MS. The site of action of epidural fentanyl in humans: the difference between infusion and bolus administration. Anesth Analg . 2003;97:1428-1438.
5. Ready LB. Acute pain: lessons learned from 25,000 patients. Reg Anesth Pain Med . 1999;24:499-505.
6. Moraca R, Sheldon D, Thirlby R. The role of epidural anesthesia and analgesia in surgical practice. Ann Surg . 2003;238:663-673.
7. Block BM, Liu SS, Rowlingson AJ, et al. Efficacy of postoperative epidural analgesia: a meta-analysis. JAMA . 2003;290:2455-2463.
8. Benzon HT, Wong HY, Belavic AMJr, et al. A randomized double-blinded comparison of epidural fentanyl infusion versus patient-controlled analgesia with morphine for postthoracotomy pain. Anesth Analg . 1993;76(2):316-322.
9. Wu CL, Cohen SR, Richman JV, et al. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids. Anesthesiology . 2005;103:1079-1088.
10. Gottschalk A, Cohen SP, Yang S, Ochroch A. Preventing and treating pain after thoracic surgery. Anesthesiology . 2006;104:594-600.
11. Chaney MA. Intrathecal and epidural anesthesia and analgesia for cardiac surgery. Anesth Analg . 2006;102:45-64.
12. Correll DJ, Viscusi ER, Grunwald Z, Moore JHJr. Epidural analgesia compared with intravenous morphine patient-controlled analgesia: postoperative outcome measures after mastectomy with immediate TRAM flap breast reconstruction. Reg Anesth Pain Med . 2001;26:444-449.
13. Nishimori M, Ballangyne JC, Low JH. Epidural pain relief versus systemic opioid-based pain relief for abdominal aortic surgery. Cochrane Database Syst Rev . 2006;19:3. CD005059
14. Gupta A, Fant F, Axelsson K, et al. Postoperative analgesia after radical retropubic prostatectomy. Anesthesiology . 2006;105:784-793.
15. Gottschalk A, Smith DS, Jobes DR, et al. Preemptive epidural analgesia and recovery from radical prostatectomy. JAMA . 1998;279:1076-1082.
16. Niiyama Y, Kawamata T, Shimizu H, et al. The addition of epidural morphine to ropivacaine improves epidural analgesia after lower abdominal surgery. Can J Anesth . 2005;52:181-185.
17. Guay J. The benefits of adding epidural analgesia to general anesthesia: a meta-analysis. J Anesth . 2006;20:335-340.
18. Christopherson R, Beattie C, Frank SM, et aland the Perioperative Ischemia Randomized Anesthesia Trial Study Group. Perioperative morbidity in patients randomized to epidural or general anesthesia for lower extremity vascular surgery. Anesthesiology . 1993;79:422-434.
19. Buggy DJ, Smith G. Epidural anaesthesia and analgesia: better outcome after major surgery? Growing evidence suggests so. BMJ . 1999;319(7209):530-531.
20. Fischer HBJ, Simanski CJP. A procedure-specific systematic review and consensus recommendations for analgesia after total hip replacement. Anaesthesia . 2005;60:1189-1202.
21. Gambling D, Hughes T, Martin G, et al. A comparison of Depodur, a novel, single-dose extended-release epidural morphine, with standard epidural morphine for pain relief after lower abdominal surgery. Anesth Analg . 2005;100:1065-1074.
22. Viscusi ER, Martin G, Hartrick CT, et aland the EREM Study Group. Forty-eight hours of postoperative pain relief after total hip arthroplasty with a novel, extended-release epidural morphine formulation. Anesthesiology . 2005;102:1014-1022.
23. Förster JG, Rosenberg PH. Small dose of clonidine mixed with low-dose ropivacaine and fentanyl for epidural analgesia after total knee arthroplasty. Br J Anaesth . 2004;93:670-677.
24. Bernard J-M, Kick O, Bonnet F. Comparison of intravenous and epidural clonidine for postoperative patient-controlled analgesia. Anesth Analg . 1995;81:706-712.
25. Auroy U, Benhamou D, Bargues L, et al. Major complications of regional anesthesia in France. Anesthesiology . 2002;97:1274-1280.
26. Wedel DJ, Horlocker TT. Regional anesthesia in the febrile or infected patient. Reg Anesth Pain Med . 2006;31:324-333.
27. Ruppen W, Derry S, McQuay H, et al. Incidence of epidural hematoma, infection, and neurologic injury in obstetric patients with epidural analgesia/anesthesia. Anesthesiology . 2006;105(2):394-399.
28. Wang LP, Hauerberg J, Schmidt JF. Incidence of spinal epidural abscess after epidural analgesia: A national 1-year survey. Anesthesiology . 1999;91:1928-1936.
29. Aromaa U, Lahdensuu M, Cozanitis DA. Severe complications associated with epidural and spinal anaesthesias in Finland 1987–1993. Acta Anaesthesiol Scand . 1997;41:445-452.
30. Hebl JR. The importance and implications of aseptic techniques during regional anesthesia. Reg Anesth Pain Med . 2006;31:311-323.
31. Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med . 2003;28:172-197.

Eric M. May, Martin L. DeRuyter

Regional analgesia has been shown to be an effective therapy for postoperative analgesia in numerous clinical scenarios. Continuous infusions of local anesthetic via perineural catheters not only capitalize on this technique but also extend the therapeutic window for several days. Patients have better outcomes, require less opioids, and can continue therapy at home in most situations. In this chapter, we describe various upper and lower extremity blocks and the placement of catheters for continuous infusions.

Whereas, historically, various approaches have been described for performing single-injection nerve blocks, when considering a catheter placement, we believe that the most reliable technique incorporates localization of the nerve via a nerve stimulator and advancement of the catheter through the needle. Various products exist; we are comfortable with the practicality, ease of use, and success rate that obtained using the Contiplex Touhy Continuous Nerve Block catheter products (B. Braun, Bethlehem, PA). Certain nerve blocks are amenable to the use of ultrasound guidance to help ensure proper needle tip location; however, this is not discussed.

After consent is obtained, patients are monitored, provided supplemental oxygen, and lightly sedated for the block procedure. Sedation generally is achieved with midazolam 1 to 2 mg and fentanyl 50 to 100 mcg. The blocks are administered in a well-lighted area, and the techniques are accomplished in a sterile fashion with the area draped. Local anesthetic at the skin site is achieved with subdermal 1% lidocaine. A small skin nick can be used to facilitate needle insertion. The stimulating needle is advanced, attempting to elicit the desired motor response. Once achieved, the milliamperage from the nerve stimulator is reduced to maintain a motor response at 0.5 mA. Following a negative aspiration, the local anesthetic is delivered in 5-ml sequential aliquots with intermittent aspiration, thus establishing an initial “block.” The agents commonly used are ropivacaine (0.5%) or bupivacaine (0.5%). The 20-gauge catheter is inserted and advanced 5 to 7 cm beyond the needle tip. The catheter is then secured, bandaged, and labeled. We follow the American Society of Regional Anesthesia and Pain Medicine (ASRA) consensus recommendations for catheter placement and removal in patients taking anticoagulant medications. These can be found with other ASRA Consensus Statements at .

Continuous analgesia is obtained by a continuous infusion of local anesthetic in addition to a multimodal analgesic regimen. The desired effect is achieved by administering a long-acting local anesthetic such as ropivacaine (0.2%), bupivacaine (0.1%), or levobupivacaine (0.1%). Compared with bupivacaine, ropivacaine has been shown to produce less motor block, which may be a desirable feature in ambulatory patients.
Generally, upper extremity infusions may start at 5 to 8 ml/hr and lower extremity infusions at 8 to 10 ml/hr. A patient-controlled analgesia (PCA) supplemental function of 4 ml every 30 minutes is included in the continuous infusion therapy, along with opioid supplementation if needed.
A multimodal approach to postoperative analgesia emphasizes the role of continuous peripheral nerve blocks with local anesthetic infusions. The protocol we follow is outlined in Figure 12–1 . This consists of acetaminophen and a daily oral nonsteroidal anti-inflammatory drug such as the cyclooxygenase-2 (COX-2) inhibitor Celebrex. Further pain-control modalities include adjustment of local anesthetic infusion rates, addition of both immediate-release and sustained-release oral narcotics, and addition of an intravenous (IV) PCA.

Figure 12–1 Postoperative analgesia algorithm in patients with peripheral perineural continuous infusion. IR, immediate release; IV PCA, intravenous patient-controlled opioid analgesia; PCA, patient-controlled supplemental analgesia; SR, sustained release; VAS, visual analog score.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.

Blockade of the upper extremity is achieved by blocking the brachial plexus. Blocks can be performed at numerous locations along the brachial plexus; some sites are more amenable than others to continuous catheter placement. In addition, each site possesses certain advantages, and disadvantages to continuous infusions, which are described for each procedure.

Interscalene Approach

Brachial plexus (C5–T1).

Open shoulder surgery, rotator cuff repair, acromioplasty, shoulder arthroplasty, and proximal upper limb surgery. 1, 2

Landmarks and patient positioning for continuous interscalene brachial plexus block are the same as those of the single-shot technique (discussed earlier). The anesthesiologist should stand at the head of the patient, facing caudad. This positioning facilitates stabilization of the needle and advancement of the catheter in a caudal direction. A 3- to 5-cm stimulating needle is inserted at a slightly caudad angle and advanced until a brachial plexus twitch is elicited ( Fig. 12–2 ). After the needle is stabilized, 20 to 40 ml of local anesthetic is delivered and the catheter is inserted.

Figure 12–2 Interscalene block.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.
The interscalene site is shallow and catheters not uncommonly leak and may easily become dislodged. In effort to minimize this complication, some providers prefer to “tunnel” the catheter. Utilizing a 3.5-inch Touhy needle, the catheter can be tracked subdermally to a distant exit site.
Postoperatively, a continuous infusion of local anesthetic is started in the recovery room and maintained on the hospital ward.

Evidence for Continuous Nerve Block
Prospective, randomized, controlled trials demonstrated that continuous interscalene analgesia reduced opioid requirements when compared with placebo. 1 For open shoulder surgery, prospective, randomized, controlled trials showed that continuous interscalene analgesia reduced the requirement for postoperative opioids over that of IV PCA. Continuous analgesia also provided better patient satisfaction and reduced opioid-related side effects. 1 A retrospective, case-controlled study demonstrated increased shoulder range of motion the day after total shoulder arthroplasty in patients with continuous interscalene nerve block when compared with patients treated with IV opioids. 3, 4

The interscalene block is unreliable in providing satisfactory anesthetic blockade to the inferior trunk of the brachial plexus. As a result, analgesia of the ulnar nerve is unreliable. In practice, a continuous catheter is not placed in this location for postoperative analgesia associated with hand surgery. 2, 5 In addition, the initial loading bolus will often produce phrenic nerve blockade (85%–100%); therefore, proper patient selection must be considered. Less frequent and less troublesome are the associated hoarseness secondary to blockade of the recurrent laryngeal nerve and Horner’s syndrome secondary to sympathetic blockade. 1

Infraclavicular Block

Brachial plexus (C5–T1).

The infraclavicular approach to brachial plexus block easily facilitates catheter placement for continuous postoperative analgesia after surgery involving the humerus, elbow, forearm, wrist, and hand. It also can provide sympathetic (and motor) block in patients suffering with vascular insufficiency or sympathetically mediated pain. 2

Landmarks are the same as for the single-shot technique (described earlier), including the medial clavicular head, coracoid process, and midpoint of the clavicle. The coracoid process can be located by elevating and raising the arm while palpating just medial to the anterior shoulder. Two common approaches have been described that facilitate catheter placement: the classic approach described by Raj and the vertical coracoid approach described by Wilson.
For the Raj approach, the patient lies supine with her or his head slightly turned away from the side of the procedure. The anesthesiologist can stand either at the head on the side of the block or on the opposite side of the block. Correct positioning by the anesthesiologist and convenient placement of equipment make catheter advancement proceed smoothly. The operative limb is abducted to 90° at the shoulder and flexed at the elbow. The axillary pulse is identified. If this is not possible, the arm can remain neutral at the shoulder; in which case, the groove between the deltoid and the pectoralis muscle is used as a landmark.
The midpoint of a line connecting the medial clavicular head and the coracoid process is identified. The axillary artery can be marked on the skin. A 4-inch nerve-stimulator needle is inserted 2 to 3 cm caudal to the midclavicular point at a 45° angle to the horizontal plane. The needle is advanced parallel to the medial clavicular head–coracoid process line toward the axillary artery pulse. Stimulation of the brachial plexus occurs soon after the pectoralis muscle twitches cease. 5 Motor activity in the hand is identified. After reducing the stimulation to less than 0.5 mA and witnessing the fade of motor activity along with a negative aspiration of blood, between 30 and 40 ml of local anesthetic is delivered and the catheter is inserted toward the apex of the axilla.
For the coracoid approach, the patient’s arm may remain adducted. The coracoid process is identified and marked. The stimulating needle is inserted perpendicular to the floor at a point 2 cm caudal and 2 cm medial from the coracoid process. The bevel is directed toward the apex of the axilla ( Fig. 12–3 ). Again, the end-point is to achieve satisfactory motor response with a 4-inch nerve-stimulating needle. Once identified, and after reducing the stimulation to less than 0.5 mA and witnessing the fade of motor activity along with a negative aspiration of blood, between 30 and 40 ml of local anesthetic is delivered.

Figure 12–3 Infraclavicular block.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.
It should be noted that accepting activity of the musculocutaneous nerve (i.e., biceps or brachialis twitch) may result in unsatisfactory blocks. In a significant percentage of patients, the musculocutaneous nerve splits early from the brachial plexus, and delivery of the local anesthetic at that site will fail to adequately block the plexus. This approach avoids phrenic nerve blockade; thus, it can be used in patients with lung disease. 2

A prospective, randomized, double-blinded, controlled trial showed that infraclavicular brachial plexus block decreased pain, opioid use, sleep disturbances, and opioid-related side effects after orthopedic procedures of the forearm and hand. 4
A randomized, double-blinded, prospective study compared the following regimens for continuous catheters placed for orthopedic surgery at or distal to the elbow: basal rate versus basal with bolus versus bolus only. Patients in the continuous infusion with patient-controlled bolus had a lower level of oral analgesic use, longer duration of infusion (for the same volume of anesthetic), and a higher satisfaction rating than those patients with a basal infusion alone. These patients also had more potent analgesia, less sleep disturbance, and higher satisfaction than the bolus group. 6

Axillary Brachial Plexus Block

Brachial plexus (C5–T1).

The axillary brachial plexus block is the most commonly used brachial plexus block for procedures on the forearm, wrist, and hand, as well as for chronic pain syndromes and vascular diseases. 2

Landmarks in the axilla are the same as those for the single-shot technique (discussed earlier) and include the axillary artery, the inferior border of the pectoralis muscle medially, and the long head of the biceps muscle laterally. Median, ulnar, and radial nerves are most compactly arranged at the proximal aspect of the axilla (lateral edge of the pectoralis minor) and diverge as they travel distally. 1 The patient is positioned supine, with the arm to be blocked abducted at 90° and the forearm flexed on the arm at 90°. The anesthesiologist is positioned on the side of the patient that is to be blocked. It is important to firmly fix the axillary artery with the palpating hand to facilitate accurate location of the catheter during placement. A 2-inch nerve-stimulator needle is inserted at a 45° angle to the skin and directed proximally ( Fig. 12–4 ). The needle is carefully advanced toward the axillary artery pulse until the required motor response is elicited at the wrist or fingers. To achieve the highest level of success, a motor response should be elicited from the nerve most involved by the surgery. After reducing the stimulation to less than 0.5 mA and witnessing the fade of motor activity along with a negative aspiration of blood, between 30 and 40 ml of local anesthetic is delivered. A catheter is advanced toward the apex of the axilla.

Figure 12–4 Axillary block.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.
Because the brachial plexus can be superficial at the level of the axilla, the catheter is sometimes tunneled for 2 to 3 cm using an 18-gauge angiocatheter. As with a single-shot axillary nerve block, the musculocutaneous nerve may need to be blocked with 5 ml of additional local anesthetic deposited in the coracobrachial muscle. 2

Case series show satisfactory analgesia after hand and forearm procedures with continuous infusions but have not compared these with IV PCA or other modalities. A study by Salonen and coworkers 7 did not show a statistical difference in analgesia or need for supplemental analgesics between patients receiving ropivacaine or saline. 1 More clinical trials are needed to investigate the efficacy of this approach.


Lumbar Plexus Block—Psoas Approach

Lumbar plexus.

Continuous lumbar plexus blocks are indicated for postoperative pain management in patients undergoing hip, femur, or knee procedures. These blocks can be combined with general anesthesia for surgery on the knee, thigh, or hip or combined with a sciatic block for most surgeries on the lower extremity. 2, 8 They are also an effective alternative to neuraxial techniques in patients in whom an epidural or a spinal block is contraindicated or technically difficult.

Blockade of the lumbar plexus has been described as an anterior “3-in-1” technique or a posterior psoas compartment technique. Our preference is to use the posterior psoas compartment approach because it has been shown to provide more reliable anesthesia of the obturator and lateral femoral cutaneous nerves. 9, 10 Another benefit of the posterior approach is that the catheter is located farther from the surgical site.
The patient is placed in the lateral decubitus position with the side to be blocked up and the hips and knees slightly flexed. Landmarks are the same as for the single-shot technique (discussed earlier) and include the iliac crest, the spinous processes, and the posterior superior iliac spine (PSIS). Slight variations in needle positioning are described in the literature. Some sources advocate needle insertion 4 or 5 cm lateral to the interspinous line at the level of a line drawn at the posterior iliac crests. 2, 5 Winnie initially suggested insertion at the intersection of a line parallel to the spine passing through the PSIS and a line joining the iliac crests. Multiple studies showed this point to be too lateral. 11 - 15 As a result, Winnie recommended a slightly medial direction to the needle after insertion. Our preference is to use the insertion point based on research by Capdevila and associates. 10 This point is at the junction of the lateral one third and the medial two thirds of a line between the spinous process of L4 and a line parallel to the spinal column passing through the PSIS. L4 is estimated to be 1 cm cephalad to the upper edge of the iliac crests ( Fig. 12–5 ).

Figure 12–5 Lumbar plexus block, psoas landmarks.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.
A 4-inch nerve-stimulator needle is inserted perpendicular to the skin while the palpating hand anchors the skin and paraspinous muscles ( Fig. 12–6 ). The needle tip orientation should be cephalad. 5 We attempt to contact the transverse process of L4, pull back slightly, and advance caudad to the transverse process until a quadriceps femoris twitch is elicited, apparent as a cephalad movement of the patella. After this motor response is observed, the current is lowered to stimulate at less than 0.5 mA. 2 Following a negative aspiration of blood, 20 to 30 ml of local anesthetic is delivered. For surgical anesthesia, 30 ml is usually necessary for a dense blockade of the lumbar plexus. 5 If the block is used in combination with a sciatic block, the volume may be reduced to minimize the risk of local anesthetic overdose.

Figure 12–6 Lumbar plexus block, psoas insertion.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.

A retrospective case series showed that continuous lumbar plexus block with sciatic nerve block and perioperative sedation was an effective alternative to general anesthesia and that it provided analgesia, adequate muscle relaxation, and postoperative pain control. 8 Decreased operative blood loss was also noted. 9
A prospective, randomized study compared postoperative analgesia and recovery after total knee replacement with a continuous lumbar plexus block via the psoas compartment with a continuous femoral nerve block and with the combination of continuous femoral and sciatic nerve catheters. The psoas block patients required less supplementary analgesia in the first 48 hours than did the femoral block patients. However, continuous femoral/sciatic patients required the least supplemental analgesia. Postoperative functional outcomes at 7 days and 9 to 12 months did not differ among groups. 15
A prospective, randomized trial comparing continuous psoas compartment lumbar plexus block to IV PCA reported better analgesia and higher patient satisfaction with a psoas compartment block. 1, 16 Another prospective multicenter trial reported 94% of patients with excellent postoperative analgesia without additional systemic opioids. 11

Differences of opinion exist on the optimal nerve-stimulator current used to elicit a motor response. One source advocates not going lower than 0.5 to 1.0 mA because the needle may be in the dural sleeve if a twitch is elicited below this level. 5
The distance from the transverse process to the lumbar plexus has been extensively studied. Capdevila and associates 10 found this distance to be 18 mm regardless of patient gender or body mass index. 11 At the L4 level, motor response is usually elicited at a depth of 6 to 8 cm, but it can be found anywhere between 5 and 10 cm. 5, 11 Some sources recommend not going beyond a depth of 9 to 10 cm without redirecting the needle. 2, 5
The optimal depth of catheter insertion has also been debated. We advocate a distance of 5 to 7 cm. 11 Some sources recommend only 3 to 4 cm in order to minimize the risk of kinking or displacement, whereas others advocate up to 8 to 10 in order to prevent catheter displacement because the skin in this region is very mobile. 2, 5

Femoral Block

Lumbar plexus (L2–L4).

Femoral nerve block produces anesthesia of the entire anterior thigh and most of the femur and knee joint, as well as the skin on the medial lower leg. It can be used for postoperative analgesia after thigh and knee surgery or combined with sedation and a sciatic nerve block for lower extremity surgery.

The patient is positioned supine with the leg to be blocked in a neutral position. The needle insertion site is 1 cm lateral to the femoral artery in the inguinal crease. The palpating hand is used to stabilize the skin prior to needle insertion. A 2-inch nerve-stimulator needle is inserted and advanced at a 45° to 60° cephalad angle until a patellar twitch is elicited. 5 After reducing the stimulation to less than 0.5 mA and witnessing the fade of motor activity along with a negative aspiration of blood, 20 to 30 ml of local anesthetic is delivered. A catheter is advanced in a cephalad direction.
The fascia iliaca approach is a modification of the femoral nerve block that may provide similar analgesia with slightly lower risk of venopuncture. A nerve stimulator is typically not required for this technique. The inguinal ligament is marked from the anterior superior iliac spine to the pubic tubercle in the supine patient. The needle insertion is 1 cm caudad to the junction of the lateral one third and the medial two thirds of this line. This site is approximately 2 to 3 cm lateral to the femoral artery ( Fig. 12–7 ). The needle is advanced at a 45° to 60° cephalad angle until two pops are felt through the fascia lata and the fascia iliaca, respectively. The angle is decreased to 30° and 20 ml of local anesthetic is injected. The catheter is advanced 15 to 20 cm cephalad past the needle tip. 1

Figure 12–7 Femoral block.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.

Prospective clinical trials have showed improved analgesia and knee range of motion with decreased incidence of nausea/vomiting when continuous femoral nerve block was compared with IV PCA. 1, 17, 18 Analgesia and range of motion were comparable with those of an epidural block. Earlier mobilization was also achieved by continuous nerve block patients who underwent total knee arthroplasty. 18, 19
A prospective, randomized trial showed that patients with continuous fascia iliaca blockade required less postoperative morphine and had improved range of motion than those receiving placebo. 20
A prospective, nonrandomized trial involving patients with total hip replacement found that continuous femoral block provided analgesia comparable with those of IV PCA and epidural blockade. Continuous nerve block was associated with a lower incidence of nausea, vomiting, pruritus, and sedation than those of IV PCA and a lower incidence of urinary retention and hypotension than epidural blockade. 21

Insertion of the continuous catheter 3 to 4 cm may make it more likely to produce lateral femoral cutaneous and obturator nerve blockade. 2

Sciatic Nerve Block—Posterior Approach (Labat)

Sacral plexus, sciatic nerve (L4–S3).

Sciatic nerve blockade produces anesthesia of the skin of the posterior thigh, hamstring, and biceps muscles, part of the hip and knee joint, and the entire leg below the knee with the exception of the skin of the medial lower leg. It can be used in combination with a continuous lumbar plexus block for hip or femur surgery or combined with a femoral or lumbar plexus block for procedures on the thigh and knee. It can also be used for amputation of the lower leg. 5

The patient is positioned in the lateral decubitus position with the side to be blocked up and a slightly forward pelvic tilt. The knees are slightly bent and the foot on the upper leg is positioned over the dependent leg so twitches can be easily observed. 5 The anatomic landmarks are the greater trochanter and the PSIS. These structures are marked and a line is drawn between them and divided in half. A perpendicular line drawn through the midpoint and extending inferiorly for roughly 4 to 5 cm identifies the needle insertion point ( Fig. 12–8 ).

Figure 12–8 Sciatic block landmarks.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.
It is important to infiltrate deeper tissues with local anesthetic to make advancement of the large, blunt-tipped needle more tolerable. As with all blocks, stabilization with the palpating hand is crucial for needle manipulation and catheter advancement. A 4-inch nerve-stimulator needle is inserted perpendicular to the skin ( Fig. 12–9 ). The bevel of the stimulating needle should be directed distally, toward the patient’s foot, to aid catheter insertion. Initially, twitches of the gluteus muscle are observed. As the needle is advanced deeper, stimulation of the sciatic nerve results in twitches of the hamstrings or foot. After reducing the stimulation to less than 0.5 mA and witnessing the fade of motor activity along with a negative aspiration of blood, 20 to 30 ml of local anesthetic is injected and the catheter is inserted.

Figure 12–9 Sciatic block insertion.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.

A prospective trial demonstrated effective postoperative analgesia in patients undergoing surgical procedures on the lower leg. 22
A prospective, randomized study compared postoperative analgesia and recovery after total knee replacement with a continuous lumbar plexus block via psoas compartment with a continuous femoral nerve block and with the combination of continuous femoral and sciatic nerve catheters. Continuous femoral/sciatic patients required the least supplemental analgesia. 15

For patients who cannot tolerate positioning for a posterior sciatic nerve block, a high lateral approach can be used. 2 With the patient supine and the leg in a neutral position, the needle insertion site is identified 3 cm caudal to the greater trochanter and 2 cm posterior to the femur. This site should be between the greater trochanter and the ischial tuberosity, which can be identified by palpating the inferior aspect of the buttocks. The hamstring muscles and the sacrotuberous ligaments attach to the ischial tuberosity; occasionally, the hamstring muscles make it challenging to easily palpate the ischial tuberosity. A 4- or 6-inch nerve-stimulator needle is inserted perpendicular to the skin with the distal tip oriented cephalad. The femur is contacted; the needle is withdrawn and redirected 20° posteriorly. The needle is advanced until a motor response is seen in the foot, usually at a depth of 8 to 12 cm. After reducing the stimulation to less than 0.5 mA and witnessing the fade of motor activity along with a negative aspiration of blood, 20 to 30 ml of local anesthetic is injected and the catheter is inserted.

Popliteal Nerve Block—Lateral Approach

Tibial and peroneal nerves.

Blockade of the branches of the sciatic nerve at the popliteal fossa provides anesthesia and analgesia for surgery on the calf, ankle, Achilles tendon, and foot. It also is effective for calf tourniquet pain. A saphenous nerve block may be combined with a popliteal nerve block to provide complete anesthesia for the lower leg. 5

The sciatic nerve usually divides into the tibial and common peroneal nerves approximately 70 mm proximal to the popliteal fossa crease. 5 The benefit of the lateral approach is that the patient can remain in the supine position, rather than having to be turned prone to perform the block via the classic posterior approach. The lateral approach also provides a more secure placement of the catheter away from the mobile knee joint. 1, 23 The knee is slightly flexed by placing a pillow under it. The groove between the vastus lateralis anteriorly and the lateral tendon of the biceps femoris posteriorly is palpated and marked. The needle insertion site lies in this groove 8 cm proximal to the popliteal fossa crease or 10 cm proximal to the superior border of the patella. 2, 5
A 4-inch nerve-stimulator needle is inserted with the tip oriented cephalad in a horizontal plane, perpendicular to the long axis of the leg ( Fig. 12–10 ). Once the femur is contacted, the needle is withdrawn and redirected 30° posteriorly. The needle is again advanced while watching for dorsiflexion or plantarflexion of the foot or toes. After reducing the stimulation to less than 0.5 mA and witnessing the fade of motor activity along with a negative aspiration of blood, 30 to 40 ml of local anesthetic is injected and the catheter is inserted.

Figure 12–10 Popliteal block, lateral approach.
Rights were not granted to include this figure in electronic media. Please refer to the printed book.
Copyright Eric L. May and Martin DeRuyter.
If this block is used in combination with a femoral nerve block, the bolus volume may be reduced in consideration of possible local anesthetic toxicity.

A prospective, nonrandomized study with a retrospective control group compared continuous popliteal nerve analgesia with IV PCA. 1, 24 The study showed that continuous nerve block provided superior analgesia, lower postoperative morphine consumption, less frequent incidence of nausea/vomiting, less urinary retention, and less sedation.
Two prospective randomized, controlled trials compared continuous popliteal nerve blockade with local anesthetic versus saline. 25, 26 Continuous nerve block patients had lower pain scores, lower opioid requirements and less opioid-related side effects, shorter length of hospital stay, and better sleep with fewer awakenings during the first 48 hours. 26


Paravertebral Nerve Block

Specific thoracic or lumbar dermatomes.

Thoracic paravertebral block provides selective unilateral anesthesia and analgesia for breast or other chest wall surgery. 27 Lumbar paravertebral block provides anesthesia and analgesia for inguinal herniorrhaphy or analgesia after hip surgery. 5 Paravertebral block can be utilized in patients in whom neuraxial techniques may be contraindicated owing to coagulopathy or intolerance of the hypotension that may result from significant sympathetic blockade.

The patient is positioned in the sitting or lateral decubitus position, similar to that required for neuraxial anesthesia. Surface bony landmarks used to identify the correct spinal level include the spinous processes, iliac crest, and the inferior tip of the scapulae, which corresponds to T7. Needle insertion should be perpendicular to the skin at a point 2.5 cm lateral to the midline. The bevel of a 2-inch nerve block needle is directed medially as the fingers of the palpating hand fix the skin to avoid horizontal skin movement. 5 The transverse process of the vertebra should be contacted and the depth noted. The needle is then withdrawn and redirected 10° inferiorly to walk off the caudal border of the transverse process. Advance the needle 1 cm deeper than the transverse process and inject 4 to 5 ml of local anesthetic after negative aspiration of blood. A catheter is advanced 3 cm past the needle tip.

A prospective, randomized study on patients having breast cancer surgery compared paravertebral nerve blocks with general anesthesia and found that nerve block patients had lower visual analog pain scores at rest and with activity, reduced opioid consumption, and lower incidence of postoperative nausea and vomiting (PONV). 28 Other studies also demonstrated the benefits of this technique for postoperative analgesia. 29

The needle should not be angled medially at insertion because of the risk of intraforaminal needle passage and nerve or spinal cord injury. 5 The depth of the transverse processes varies with patient body habitus and the level at which the block is performed. The deepest levels are at the high thoracic (T1–2) and low lumbar levels where contact occurs at a depth of 6 to 8 cm. The shallowest depth of contact occurs at 2 to 4 cm for the midthoracic levels (T5–10). 5


Types of catheters for continuous peripheral nerve blockade include 20-gauge multiorifice epidural catheters, 20- or 21-gauge epidural catheters with wire stylet, and 21-gauge stimulating catheters. 2 Inaccurate catheter placement is not uncommon. Some clinicians first insert the catheter and then administer a bolus of local anesthetic via the catheter in an effort to avoid this problem. The stimulating catheters deliver current to the distal tip to provide feedback on the position of the tip relative to the nerve before local anesthetic injection. Although some evidence suggests this may improve accuracy of catheter placement, no investigations have yet shown definite increased accuracy of catheter placement using stimulating catheters over that of nonstimulating catheters. 30, 31

Infusion Devices
Options for infusion devices for postoperative inpatient and outpatient infusions include disposable elastomeric devices, spring-powered pumps, and electronic infusion pumps. Elastomeric devices provide a more rapid than expected basal rate initially, return to their expected rate within 2 to 12 hours, and increase to a higher rate before reservoir exhaustion. These devices can provide bolus-only dosing by allowing the patient to manually release a clamp on the catheter. The risk of this method is that if the patient forgets to reclamp the tubing, the entire reservoir of local anesthetic can be delivered in less than an hour. 30
Spring-powered pumps initially provide a greater than expected basal rate with steady decreases to a less than expected rate by reservoir exhaustion. It is unknown whether variability in basal rate has affected outcomes. A manually delivered bolus dose can be set with a lock-out interval. Settings are preset by the manufacturer. Both spring and elastomeric pumps can be refilled. 30
Electronic infusion pumps provide the most accurate and consistent basal rates over the duration of the infusion. These pumps can be programmed by the clinician or patient (if clinicians permit) and allow the patient to deliver PCA boluses electronically by pressing a button. Electronic pumps have alarms that can both notify the patient of a malfunction and sound a false alarm. Nonelectronic pumps cannot alarm. Published data on pump reliability are limited. 30


1. Liu S, Salinas F. Continuous plexus and peripheral nerve blocks for postoperative analgesia. Anesth Analg . 2003;96:263-672.
2. Chelly J, Casati A, Fanelli G. Continuous Peripheral Nerve Block Techniques, An Illustrated Guide. London: Mosby, 2001;3-84.
3. Ilfeld BM, Wright TW, Enneking FK, Morey TE. Joint range of motion after total shoulder arthroplasty with and without a continuous interscalene nerve block: a retrospective case-controlled study. Reg Anesth Pain Med . 2005;30:429-433.
4. Ilfeld BM, Morey TE, Wright TW, et al. Continuous interscalene brachial plexus block for postoperative pain control at home: a randomized, double-blinded, placebo-controlled study. Anesth Analg . 2003;96:1089-1095.
5. Hadzic A, Vloka J. New York School of Regional Anesthesia Peripheral Nerve Blocks, Principles and Practice. New York: McGraw-Hill, 2004;79-315.
6. Ilfeld BM, Morey TE, Enneking FK. Infraclavicular perineural local anesthetic infusion: a comparison of three dosing regimens for postoperative analgesia. Anesthesiology . 2004;100:395-402.
7. Salonen M, Haasio J, Bachman M, et al. Evaluation of efficacy and plasma concentrations of ropivacaine in continuous axillary brachial plexus block: high dose for surgical anesthesia and low dose for postoperative analgesia. Reg Anesth Pain Med . 2000;25:47-51.
8. Stevens RD, Van Gessel E, Flory N, et al. Lumbar plexus block reduces pain and blood lLoss associated with total hip arthroplasty. Anesthesiology . 2000;93:115-121.
9. Seeberger MD, Urwyler A. Paravascular lumbar plexus block: block extension after femoral nerve stimulation and injection of 20 vs. 40 ml mepivacaine 10 mg/ml. Acta Anaesthesiol Scand . 1995;39:769-773.
10. Capdevila X, Macaire P, Dadure C, et al. Continuous psoas compartment block for postoperative analgesia after total hip srthroplasty: new landmarks, technical guidelines, and clinical evaluation. Anesth Analg . 2002;94:1606-1613.
11. Birnbaum K, Prescher A, Hessler S, Heller KD. The sensory innervation of the hip joint: an anatomical study. Surg Radiol Anat . 1997;19:371-375.
12. Farny J, Drolet P, Girard M. Anatomy of the posterior approach to the lumbar plexus block. Can J Anaesthesiol . 1994;41:480-485.
13. Deitemann JL, Sick H, Wolfram-Gabel R, et al. Anatomy and computed tomography of the normal lumbosacral plexus. Neuroradiology . 1987;29:58-68.
14. Morin AM, Kratz CD, Eberhart LHJ, et al. Postoperative analgesia and functional recovery after total-knee replacement: comparison of a continuous posterior lumbar plexus (psoas compartment) block, a continuous femoral nerve block, and the combination of a continuous femoral and sciatic nerve block. Reg Anesth Pain Med . 2005;30:434-445.
15. Buckenmaier CC, Xenos JS, Nilsen SM. Lumbar plexus block with perineural catheter and sciatic nerve block for total hip arthroplasty. J Arthroplasty . 2002;17:499-502.
16. Chudinov A, Berkenstadt H, Salai M, et al. Continuous psoas compartment block for anesthesia and perioperative analgesia in patients with hip fractures. Reg Anesth Pain Med . 1999;24:563-568.
17. Ganapathy S, Wasserman R, Watson JT, et al. Modified continuous femoral three-in-one block for postoperative pain after total knee arthroplasty. Anesth Analg . 1999;89:1197-1202.
18. Capdevila X, Barthelet Y, Biboulet P, et al. Effects of perioperative analgesic technique on the surgical outcome and duration of rehabilitation after major knee surgery. Anesthesiology . 1999;91:8-15.
19. Singelyn F, Deyaert M, Pendeville E, et al. Effects of intravenous patient-controlled analgesia with morphine, continuous epidural analgesia, and continuous three-in-one block on postoperative pain and knee rehabilitation after unilateral total knee arthroplasty. Anesth Analg . 1998;87:88-92.
20. Chelly JE, Greger J, Gebhard R, et al. Continuous femoral nerve blocks improve recovery and outcome of patients undergoing total knee arthroplasty. J Arthroplasty . 2001;16:436-445.
21. Singelyn F, Gouverneur JM. Postoperative analgesia after total hip arthroplasty: IV PCA with morphine, patient-controlled epidural analgesia, or continuous “3-in-1” block—a prospective evaluation by our acute pain service in more than 1,300 patients. J Clin Anesthesiol . 1999;11:550-554.
22. Grant SA, Nielsen KC, Greengrass RA, et al. Continuous peripheral nerve block for ambulatory surgery. Reg Anesth Pain Med . 2001;26:209-214.
23. Hadzic A, Vloka JD. A comparison of the posterior versus lateral approaches to the block of the sciatic nerve in the popliteal fossa. Anesthesiology . 1998;88:1480-1486.
24. Singelyn F, Aye F, Gouverneur JM. Continuous popliteal sciatic block: an original technique to provide postoperative analgesia after foot surgery. Anesth Analg . 1997;84:383-386.
25. White PF, Issioui T, Skrivanek GD, et al. The use of a continuous popliteal sciatic nerve block after surgery involving the foot and ankle: does it improve the quality of recovery? Anesth Analg . 2003;97:1303-1309.
26. Ilfeld BM, Morey TE, Wang RD, Enneking FK. Continuous popliteal sciatic nerve block for postoperative pain control at home: a randomized, double-blinded, placebo-controlled study. Anesthesiology . 2002;97:959-965.
27. Klein SM, Evans H, Nielsen KC, et al. Peripheral nerve block techniques for ambulatory surgery. Anesth Analg . 2005;101:1663-1676.
28. Naja MZ, Ziade MF, Lonnqvist PA. Nerve-stimulator guided paravertebral blockade vs. general anaesthesia for breast surgery: a prospective randomized trial. Eur J Anaesthesiol . 2003;20:897-903.
29. Greengrass R, O’Brien F, Lyerly K, et al. Paravertebral block for breast cancer surgery. Can J Anaesth . 1996;43:858-861.
30. Ilfeld BM, Enneking FK. Continuous peripheral nerve blocks at home: a review. Anesth Analg . 2005;100:1822-1833.
31. Salinas FV, Neal JM, Sueda LA, et al. Prospective comparison of continuous femoral nerve block with nonstimulating catheter placement versus stimulating catheter-guided perineural placement in volunteers. Reg Anesth Pain Med . 2004;29:212-220.

Jianguo Cheng, Juan Cata

Interpleural anesthesia provides analgesia over the chest wall and upper abdomen. It involves placement of a catheter into the tissue plane within the chest wall such that a single injection or continuous infusion of local anesthetics spreads to several intercostal and paravertebral nerves. The terms intrapleural and interpleural have been used interchangeably, but the latter is preferred. It was first described in 1986 by Reiestad and Stromskag 1 and has been used for management of acute pain associated with multiple rib fractures, 2 upper abdominal surgeries, 3 - 8 mastectomy, 9 thoracotomy, 10 - 17 nephrostomy and nephrolithotomy, 18, 19 extracorporeal shock wave lighotripsy, 20 esophagectomy, 21 thoracoscopic sympathectomy, 22 chemical pleurodesis, 23 and acute herpes zoster. 24, 25 It has also been utilized in patients with pain associated with many other conditions, 26 - 33 such as malignancy, chronic pancreatitis, nephrolithotomy, acute herpes zoster, postherpetic neuralgia, and complex regional pain syndrome of the upper extremities. Whereas this technique is mostly used in adults, it can be performed safely in the pediatric population 17, 33, 34 ( Table 13–1 ).
Table 13–1 Applications of Interpleural Anesthesia Pain States Reference Acute Pain
Multiple rib fractures
Thoracoscopic sympathectomy
Transhepatic biliary procedures
Percutaneous nephrostomy
Extracorporeal shock wave lithotripsy
Acute herpes zoster
Chemical pleurodesis
Luchette et al, 1994
Stromskag et al, 1988
Higgins et al, 2005
Inderbitzi et al, 1992
Assalia et al, 2003
Razzaq et al, 2000
Trivedi et al, 1990
Saied et al, 1991
Reiestad et al, 1989
Thwaites et al, 1995
Sherman et al, 1988 Chronic Pain
Hepatic metastatic disease
Chronic pancreatitis
Postherpetic neuralgia
Complex regional pain syndrome
Tumor invasion brachial plexus
Upper limb ischaemia
Waldman et al, 1989
Vercauteren et al, 1994
Dionne et al, 1992
Sihota et al, 1988
Shantha, 1991
Dionne et al, 1992
Perkins, 1991 Pediatric Pain
Insertion peritoneal dialysis catheter
Weston et al, 1995
Swinhoe et al, 1994
Although thoracic epidural anesthesia may provide equally effective or superior analgesia over the chest wall and upper abdomen compared with interpleural anesthesia, it cannot replace the use of interpleural anesthesia 2, 11 in many circumstances. Epidural anesthesia may be impossible in many cases owing to such factors as obesity, scoliosis, difficult positioning, and high risk of neuroaxial coagulopathy. Compared with intravenous infusion of opioids, interpleural anesthesia can provide better pain control and fewer side effects. 11 Also, interpleural analgesia is equally, if not more, effective than intercostal nerve block and cryoanalgesia. 11, 16

The intercostal space of the posterior chest wall has three layers: the external intercostal muscle; the posterior intercostal membrane, which is the aponeurosis of the internal intercostal muscle; and the intercostalis intimus muscle, which is a continuation of the transversus abdominis. The intercostal nerves lie in between the posterior intercostal membrane and the intercostalis intimus. The posterior intercostal membrane forms a complete barrier beneath the external intercostal muscle, whereas the intercostal intimus is incomplete and allows fluid to pass freely into the subpleural space. 35
Interpleural analgesia can thus be accomplished by placing a catheter either deep into the internal intercostal muscle but superficial to the parietal pleura or between the parietal and the visceral layers of the pleura. The local anesthetic can diffuse to adjacent intercostal nerves and paravertebral nerves in either case, but central spreading of anesthetics to the epidural or subarachnoid space does not usually occur. The mechanism of action for interpleural analgesia is, therefore, dependent on diffusion of the local anesthetic to the intercostal and paravertebral nerves. The number of intercostal and paravertebral nerves affected depends on the location of the catheter, the volume injected, and effects of gravity.
The intercostal nerves are branches of the anterior divisions of the thoracic spinal nerves and innervate the thoracic and abdominal walls. Each intercostal nerve runs in a groove in the inferior aspect of the rib along with the intercostal artery and vein. The interpleural space is located between the parietal and the visceral pleura, which are delicate serous membranes that cover the surface of the lungs and the inner surface of the chest wall. The space is 10 to 20 microns in width and has a static volume of 0.1 to 0.2 ml/kg. The microvilli-covered mesothelial surface of the parietal pleura facilitates the absorption of the local anesthetic and its diffusion to the subpleural space. The pleura receive nerve innervation from the phrenic and sympathetic nerves. Interpleural administration of anesthetics may, therefore, affect neural conduction of both nerve types.

An epidural catheter is commonly inserted through a Tuohy needle at a level between T6 and T8. The entry point is anywhere between 8 cm lateral to the posterior midline and the posterior axillary line. A lateral decubitus position is often taken with the affected side up. The level of each rib is palpated and marked and the entry point determined. In contrast to the entry point at the inferior border of the rib for individual intercostal nerve block, the entry point for interpleural anesthesia can be at the superior border of the selected rib to avoid trauma to the intercostal nerve and blood vessels by the large Tuohy needle used for interpleural anesthesia.
The skin is prepared with aseptic technique, and a skin wheal is raised with local anesthetic through a 22- to 25-gauge needle. A Tuohy needle is then introduced perpendicularly with the bevel facing superficially. It is “walked off ” the superior edge of the rib and advanced to a position either just past the posterior intercostal membrane or between the parietal and the visceral pleural space. The first position is often signified by a “pop” when the needle pierces through the posterior intercostal membrane, whereas the pleural space can be identified with a loss of resistance technique that is similar to that of epidural anesthesia. 36 The pleural pressure remains negative throughout the respiratory cycle, whereas the pressure in the intercostal space oscillates from negative to positive at the end of inspiration and expiration, respectively. Spontaneous ventilation should be maintained during the procedure. Controlled ventilation increases the risk of tension pneumothorax during positive-pressure ventilation.
Once the pleural space is found, an epidural catheter is advanced 4 to 6 cm past the tip of the needle and fixed in position as the needle is withdrawn. For single injection, 20 to 25 ml of 0.25% bupivacaine can achieve a mean duration of analgesia of 7 hours (range 2–18 hr). 1, 4 Plasma concentration of the local anesthetic peaks at 15 to 20 minutes after injection. Adding epinephrine to the solution slightly delays and reduces the peak plasma concentration. For continuous infusion, a rate of 0.125 ml/kg/hr is usually employed. A subcutaneous tunneled interpleural catheter can be placed in patients when a long-term infusion of analgesic is desired.

Bupivacaine is the most commonly used agent, and lidocaine is an alternative. Single or repeated injections of 0.25% to 0.5% in volumes of 10 to 40 ml are usually performed. A single injection of 20 ml of 0.5% of bupivacaine with 5 mcg/ml of epinephrine produces a cutaneous sensory block that extends from dermatome T4 to T10 or even a more extensive block from dermatome T1 to T12. 37 The onset of analgesia after a single injection of 20 ml of 0.5% bupivacaine with epinephrine (1:200,000) is within 1 to 3 minutes. Complete pain relief is achieved within 30 minutes, and the mean duration of the analgesic block is 7 hours. Quicker onset of interpleural blockade is achieved with more concentrated solutions of bupivacaine, more alkaline pH, and a mixture of lidocaine and bupivacaine. 38 Repeated intrapleural bupivacaine administration may be used without signs of toxicity and accumulation. Continuous infusion of bupivacaine and lidocaine can be used up to 72 hours for postoperative pain. Lower concentrations from 0.125% to 0.375% of bupivacaine are administered and usually preceded by an initial bolus of 20 ml of 0.5%. There is no clinical evidence of toxicity at a mean steady-state plasma concentration of 2 mg/L bupivacaine.
There is no consistent level of dermatomal analgesia when 2% lidocaine with 1:200,000 epinephrine is injected intrapleurally. After a single injection of lidocaine, the systemic absorption is rapid and is not affected by the coadministration of epinephrine. Lidocaine is also found in cerebral spinal fluid, most likely secondary to diffusion from the blood stream. A continuous infusion of 2% lidocaine with 1:200,000 epinephrine can also be used during the first 48 to 72 hours after thoracic or upper abdominal surgery even though the effect of epinephrine on local anesthetic absorption is not clear.
The addition of opioids such as fentanyl 2 mcg/ml to local anesthetic solution for interpleural anesthesia improves pain control after thoracotomy and decreases the consumption of intravenous narcotics. Also, the administration of opioids alone may be more effective than systemic opioids. However, intrapleural opioid analgesia is no more effective than the analgesia provided by local anesthetics. Interpleural opioids may act on opioid receptors in the peripheral nerves. Clonidine, a α 2 -adrenergic receptor agonist, has also been used interpleurally as an adjuvant analgesic to synergistically increase the efficacy of interpleural anesthesia without complications.
Interpleural injection of bupivacaine and lidocaine does not significantly affect heart rate, blood pressure, and cardiac output. 39 However, the coadministration of 20 ml of 0.5% of bupivacaine with 5 mcg/ml of epinephrine can increase the cardiac output by 15% within 15 to 20 minutes after the injection. 37 Compared with epidural analgesia, interpleural block produces a lower incidence of hypotension and tachycardia. 2, 40 Unilateral interpleural analgesia improves the forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV 1 ) after cholecystectomy or pneumonectomy. 5 This is not seen, however, in patients with chronic pain.
The presence of large amounts of intrapleural fluids such as blood or empyema may decrease the efficacy of the block. The interpleural anesthetic may be diluted or trapped in the presence of binding proteins in such fluids. A significant amount of the local anesthetic may be lost in the presence of multiple chest tubes. The use of two interpleural catheters (one superior and one inferior) may help to improve analgesia in certain circumstances. Interpleural anesthesia (in efforts to achieve significant sensory blockade) is not recommended for patients who undergo pneumonectomy because high plasma concentrations of local anesthetics may be expected in such patients.

Patients need to be monitored closely for potential complications ( Box 13–1 ). Pneumothorax is a significant risk of interpleural anesthesia if a chest tube is not already in place. Hemothorax and chest wall hematoma can result from incidental damage to the intercostal vasculature. Intrabronchial injection has been reported after interpleural blockade. Horner’s syndrome can result from unilateral sympathetic blockage, particularly after injection of a relatively large volume of local anesthetic. Systemic absorption is significant with continuous infusion for more than 2 days. Fortunately, clinical reports of systemic toxicity, which may lead to seizures, are rare. Spread of local anesthetic to epidural space is rare and usually insignificant. Catheter displacement can occur and may be prevented by the use of a suture to anchor the catheter to the chest wall. Infection is a risk when the catheter is indwelling. Although this technique has been performed in patients with a large variety of pulmonary conditions, it is not recommended for those with pleural adhesions, empyema, large pulmonary bullae, or bronchopleural fistulas.


• Tension pneumothorax
• Hemothorax
• Chest wall hematoma
• Intrabronchial injection
• Horner’s syndrome
• Systemic toxicity (seizures)
• Catheter migration
• Infections

In summary, interpleural analgesia provides excellent analgesia over the chest wall and upper abdomen and is applicable to a large variety of acute and chronic pain conditions. It is relatively safe and convenient to use in many cases when epidural anesthesia is not feasible or appropriate. The anatomic feature of the posterior chest wall allows interpleurally administered local anesthetics to reach many levels of the intercostal and paravertebral nerves. Injection or continuous infusion of a local anesthetic can be supplemented with epinephrine, opioids, or clonidine. The use of interpleural anesthesia may also significantly improve respiratory function. It has minimal effects on hemodynamic stability and rarely leads to systemic toxicity. Nevertheless, patients should be closely monitored for potential complications such as pneumothorax.


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20. Reiestad F, McIlvaine WB. Interpleural anesthesia for extracorporeal shock wave lithotripsy. Anesth Analg . 1989;69:551-552.
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30. Shantha TR. Causalgia induced by telephone-mediated lightning electrical injury and treated by interpleural block. Anesth Analg . 1991;73:507-508.
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Winston C.V. Parris, Ike Eriator

The American Cancer Society estimated that, globally, there will be more than 12 million new cancer cases in 2007 and that about 20,000 people will die from cancer every day. By 2050, there will be 27 million new cases worldwide and 17.5 million deaths annually. 1 According to the National Cancer Institute Surveillance Epidemiology and End Result report, 1,437,180 people in the United States will be diagnosed with cancer in 2008, and 565,650 people will die from cancer. 2 Cancer remains a major cause of death in the developed world and is rapidly achieving that status in the developing world. About 1 in 10 persons dies from cancer in the rest of the world, and 1 in 4 patients die from cancer in the United States. Approximately 30% of patients with cancer have pain early in the course of the disease, and about 75% to 90% of cancer patients have pain by the time the disease has reached advanced stages. 3 About 50% of all patients diagnosed with cancer will need physician-prescribed analgesia. 4 The pain associated with cancer may be localized, or as in the majority of cases, it occurs in multiple sites, or even worse, it may be disseminated. The more severe forms of cancer pain seem to occur in patients whose cancer is either untreated or unresponsive to treatment.
Despite the increasing prevalence of cancer, improvements in the detection and treatment of most cancers have resulted in a significant increase in survival rates. 5 Estimates indicate that about 10 million people are living with cancer at the present time. 6 Pain in cancer survivors is also becoming increasingly significant. The prevalence of chronic pain in breast cancer survivors is estimated to be at least 50%. The incidence of pain after treatment for head and neck cancer may be as high as 50%, and long-term disability in these patients has been correlated with high pain scores. 7 For many cancer survivors, pain is a pivotal symptom. It is a constant reminder of their history and the possibilities of the future. Cancer pain negatively affects a patient’s physical activity, social interaction, will to live, and quality of life. 8 - 10 The effective management of pain is, therefore, central to the medical care that should be provided to all cancer patients.
Sadly, a few oncologists in some well-known medical centers are reluctant to refer cancer patients with severe pain to pain centers or pain clinics, and occasionally, when they do, the disease has progressed so far that only palliative measures or hospice interventions are appropriate at that time. It is hoped that with more education, professional dialogue, and collaborative interactions, previously held biases, perceptions, or justifiable concerns may be addressed, and all clinicians directly or indirectly associated with the management of cancer pain may work together in a mature, scholarly, and efficient manner to address the needs of the cancer pain patient. An interdisciplinary approach involving pharmacologic treatment options, interventional measures, physical medicine and rehabilitation approaches, as well as behavioral interventions will produce the best outcomes. Other specialists including counselors, social workers, and chaplains need to be involved, as appropriate.
One of the satisfying aspects of cancer pain management today is the fact that, globally, strategies are evolving that are attempting to address the inadequacies of cancer pain treatment. Cancer is a worldwide problem that appears to be underreported in countries where wars, famine, high infant mortalities, malaria, human immunodeficiency virus (HIV) and acquired immunodeficiency disease (AIDS), malnutrition, and reduced life expectancy are high. Even in these countries, cancer pain exists, but understandably, it is not a health care priority. The World Health Organization (WHO), the Pan-American Health Organization (PAHO), and some agencies of the United Nations have attempted to address the major issues relating to the undertreatment of cancer pain; these actions are producing some good results. A very simple but important result is the increased availability of morphine and related opioids and a decrease in the bureaucracy associated with the importation of these drugs into a country. This action has made it possible to begin to offer patients some modicum of relief from cancer pain.
Within the United States, many organizations have attempted to address the undertreatment of cancer pain and have largely succeeded in making cancer pain treatment mandatory and not optional. These organizations include the American Pain Society, the American Academy of Pain Medicine, the International Association for the Study of Pain, the Ad Hoc Committee on Cancer Pain of the American Society of Clinical Oncology, and others. Progress has been made, but much more needs to be done. It is important to control cancer pain for many reasons, including
1. It is the right, ethical, and humanitarian thing to do.
2. Unrelieved cancer pain results in unnecessary suffering.
3. Continued pain results in decreased physical activity, anorexia, and sleep deprivation, which collectively produce debilitation.
4. Continued pain has psychological implications that may result in hopelessness, despair, and loss of the will to live.
5. Prolonged pain may cause cancer patients to eventually reject active oncologic treatment.
6. Chronic cancer pain diminishes participation in and enjoyment of the activities of daily living.
7. Cancer pain promotes loss of control, diminishes autonomy, and adversely affects quality of life.
8. Severe intractable cancer pain may produce depression and, in a few cases, promote suicide or consideration of suicide.

There are several reasons for the untreatment of cancer pain, and some of these may be related to
1. Health care providers.
2. Health care system.
3. Patients.
4. Patients’ families.
5. A combination of some or all of these.
Some of the common reasons for inadequate pain management from a health care provider’s perspective are
1. Deficient education and inadequate training and knowledge of pain medicine.
2. Misinformed concern about regulatory issues relating to controlled substances.
3. Inadequate or nonassessment of pain.
4. Unrealistic and overexaggerated fear of addiction.
5. Confusion over the clinical implication of tolerance, dependency, habituation, and tachyphylaxis.
The other major impediments to effective cancer pain management arise from
1. Patients’ reluctance to report pain and their inhibition to take opioids or to be known to have taken opioids.
2. Unduly restrictive laws governing the regulation of opioids and related drugs.
3. Inappropriate reimbursement by Medicare, Medicaid, and other third-party payors for services rendered for cancer pain management.
4. General underfunding, low prioritization, and underappreciation of the benefits of cancer pain management.
Many of these problems may be solved with education; dissemination of relevant and current information; open, unbiased, collegial interactions; and governmental goodwill and responsiveness. Health care providers, especially physicians and nurses, have to increase their knowledge base on the principles and fundamentals of pain management in general and cancer pain management in particular. A detailed understanding of the pharmacology of opioids, sedatives, analgesics, hypnotics, anticonvulsants, and other drugs used in pain management is essential. Depending on individual specialty and on practice style, knowledge of the available basic and interventional pain procedures to control pain in cancer pain patients is useful not only to treat the patient but also to implement appropriate referrals to credentialed pain clinicians.

There may be many causes of cancer pain, and in some patients, there may be multiple causes (multiple types of pain and multiple locations are also not uncommon). The common causes of cancer pain include
1. Pain due to tumor, including progression, tumor invasion, and related pathology. Examples include the Pancoast syndrome, bony metastasis, and cerebral metastasis. Tumors may invade neural tissues and lead to various plexopathies. Tumors may also produce compression of structures (e.g., the intestine) or structural erosions (e.g., of the skin). Whenever a cancer patient or survivor has a significant exacerbation of pain, the possibility of a recurrence must be considered.
2. Pain due to diagnostic testing or treatment, including surgery, chemotherapy, or radiation therapy. Patients are known to be afraid to complain of pain to their provider because of fear of the tests that may be ordered. Bone marrow aspirations, spinal puncture, and biopsies can be significant sources of pain. Procedural pain is very common after surgery for tumor or tumor-related effects. Good acute pain control may reduce the incidence of chronic pain in cancer survivors. 11 Phantom pain, radiation-induced pain, and chemotherapy-induced polyneuropathy are common after therapy. Thirty percent to 70% of patients treated with chemotherapy will develop chemotherapy-induced peripheral neuropathy (CIPN). 5 Osteonecrosis is a well-known complication of steroid therapy. The weight-bearing joints are most commonly affected, and surgery is often required to relieve pain and restore function. Osteonecrosis may also follow the use of other chemotherapeutic agents and radiation. Late effects of radiation include neural damage and connective tissue fibrosis. Radiation-induced brachial plexopathy can follow treatment for breast cancer. Chronic pelvic pain may follow prostate brachytherapy. 12 About 20% of patients treated with brachytherapy complain of dysuria 1 year after therapy. Radiation myelopathy may follow injury to the spinal cord from radiation. It may present with pain or dysesthesia at or below the level of injury. Late postradiation chronic pain syndromes have onset that is greatly delayed, often by several years, from the radiation. 6
3. Pain due to associated infections or immune deficiency states. The median age for diagnosis of cancer is about 67 years. Of all cancers, 76.7% tend to occur in people who are 55 years of age or older. 1 Immunomodulation due to the cancer or the therapy can increase the predisposition of this age group to painful conditions such as herpes zoster and postherpetic neuralgia.
4. Pain due to other cancer-associated symptoms such as general malaise, cachexia, nausea, constipation, weight loss, shortness of breath, anxiety, and myofascial dystrophy. These symptoms can aggravate the pain, and pain treatment may also exacerbate some of these symptoms. For instance, constipation and nausea may be increased by opioid therapy.
5. Pain due to preexisting or coexisting medical conditions unrelated to the cancer (e.g., arthritis, low back pain, and migraines). Having cancer does not make any patient immune from such coexisting or preexisting painful medical conditions.

Improved survival in cancer patients is mainly due to early detection and aggressive treatment. Widespread screening for breast, prostate, and colon carcinomas has improved early detection and effective treatment. Effective early screening techniques are yet to be developed for some cancers including those of the lung, pancreas, and ovaries, and these have poor long-term survival. 5 In such patients with cancer of the lung, pancreas or ovaries, pain is often the presenting symptom.
The kind of pain occurring in a particular patient depends on the cancer type and stage of disease. Patients with more advanced disease tend to have more severe pain. Further, some cancers (e.g., pancreatic and ovarian) tend to metastasize early and disseminate very rapidly, whereas others may progress more slowly. When pain occurs in patients with slow progressing cancers or in patients whose life expectancy is greater than 6 months, great opportunity exists for offering therapeutic strategies that may be effective in controlling cancer-related pain. That is not to say that if life expectancy is short, these patients are not treated. On the contrary, the impact of successful therapy is more dramatic (both to the patient and to the treating providers) because the relief provided to the suffering patient is so important that it allows those patients and their loved ones to meaningfully enjoy the last days and to prepare for the inevitable death and dying process in a dignified way. In these patients, different approaches are warranted and available to effectively manage pain. The goal is to evaluate the disease and its progression, to assess pain, and to develop a therapeutic plan of pain management applicable to and effective for the individual patient.
Primary tumors can be treated by surgery or radiation, thus decreasing associated pain. But metastasis to other organs, which facilitates tumor-induced pain, is the most difficult to treat. Metastasis to the bone is the most frequent cause of pain in cancer patients, usually due to direct tumor invasion 13 or distant metastasis. Bone pain is often the most common presenting symptom indicating spread beyond the primary site. Bony metastasis most often occurs from the breast, prostate, lungs, and ovaries. Many patients experience pain even before the bony metastasis becomes radiologically evident. The pain is often described as “dull,” “constant,” and “gradually increasing in intensity.”

Pain Assessment
Regular pain assessments and reassessment of cancer pain patients should be done and recorded. As with any clinical syndrome, assessment and measurement are critical to document and quantify the condition. That measurement is used to assess the efficacy, or lack thereof, of a particular therapy and also to gauge the progress of the disease. In pain syndromes, there are no generally accepted or reproducible objective measures of pain. Nevertheless, many subjective instruments have some utility in assessing cancer pain patients. All these instruments have limitations that may be affected by patient bias, physician/nurse bias, patient literacy, patient level of awareness, and other factors, and the resultant assessment may be flawed. Pain is subjective. The psychosocial and existential components should be assessed. Otherwise, treatment failures may result despite the appropriateness of the chosen modalities to address the physical component. Diagnostic evaluations may be necessary, if not already done, to better understand the pathogenesis, extent, and spread of the neoplastic process.
As part of the pain assessment, it is imperative to have a detailed history and physical examination with a diagnosis and plan of management that includes emphasis on objectives of therapy, life expectancy, and treatment options appropriate for the occasion. Assessment should include the severity, location, quality, timing, and modulating factors of the pain.
The commonly used intensity scale instruments include
1. Numerical pain scale.
2. Visual analog scale (VAS).
3. Simple descriptive pain scale.
4. Subjective Pain Intensity Rating (SPIR).
These scales are helpful in monitoring the effectiveness of treatment. Many other instruments are used to assess pain in chronic pain patients, but they may be unwieldy, inappropriate, or too cumbersome for the cancer pain patient. Our personal preference is the SPIR, which simply asks the patient to rate his or her pain on a scale of 0 to 10, with 0 being no pain and 10 equivalent to the worst imaginable pain. A pain diary kept by the patient may provide more detailed information relating to the effects of activities on the pain, the effects of the medication administered, and the need to add or adjust rescue medication.
Pain assessment should be ongoing and should be recorded after each therapy to assess therapeutic efficacy. It is interesting to note that the Joint Commission for Accreditation of Hospital Organization (JCAHO) has mandated that pain assessment is no longer optional but is mandatory. The Veterans Administration Hospital systems have added pain assessment as the “fifth vital sign,” after pulse, respiration, blood pressure, and temperature. In legal circles, it is reported that a few cases have been successfully litigated against providers who did not assess cancer patients’ pain and did not treat the pain. These events may hopefully sensitize health care providers to the need to assess patients with pain and to offer appropriate therapy or obtain help (e.g., referral/consultation).
In assessing the cancer patient, it is important to recognize that there are specific pain syndromes that may be associated with particular neoplasms. When these pain syndromes are recognized, effective therapy may be offered early, and as a consequence, unnecessary pain and suffering may be prevented. Some of these syndromes may result from spinal cord compression, invasion of nerves and plexuses, metastatic involvement, and visceral spread. Brachial plexopathy may be secondary to a direct extension from a Pancoast tumor or lymph node metastasis from breast cancer or a lymphoma. Lumbosacral plexopathy may be due to a direct extension from colorectal, prostate, or cervical cancer or to metastasis from a lymphoma or breast cancer. Cervical plexopathy may be due to a local extension of a head and neck cancer or lymph node metastasis. Cranial nerve neuralgia may occur owing to cancers of the head and neck or leptomeningeal metastasis. Paraneoplastic peripheral neuropathy may be due to small cell lung cancer. Central pain may be due to spinal cord compression or cerebral metastasis.
Radiation therapy may be accompanied by myelopathy, plexopathy, or neuropathy, depending on the site. Surgery may be followed by phantom pain, post-thoracotomy pain, or postamputation pain. Several chemotherapeutic agents, including the vinca alkaloids, taxanes, and platinium-based compounds, can induce pain and a sensory neuropathy referred to as chemotherapy-induced peripheral neuropathy (CIPN). CIPN involving C- and Aδ-sensory nerve fibers is often characterized by development of a tingling and burning pain in the extremities and increased sensitivity to cold. Corticosteroids may produce proximal myopathy and a burning perineal sensation.
Breakthrough pain (BTP) is any transient and clinically significant pain that rises over adequately controlled baseline pain. 14 BTP is a serious clinical problem that affects about 50% to 90% of patients with cancer pain (usually roughly two thirds). It tends to be associated with more severe pain, reduced responsiveness to opioid medication, and pain-related psychological distress and functional impairment. 15 Most patients experience about three BTP episodes a day. Most of the episodes last less than half an hour and can reach peak intensity within a few minutes. BTP may be predictable or can occur without warning. End-of-dose failure BTP manifests as pain occurring at the end of the dosing interval.

The cancer pain pathway may be viewed, for treatment purposes, in terms of the processes of transduction, transmission, modulation, and perception. Analgesic agents work at various levels of this pathway. Current approaches to cancer pain management may best be understood in terms of a mechanistic-based approach along this pathway. For instance, painful visceral sensation from the abdomen and pelvis is transmitted along the sympathetic nervous system. These relay in paired paravertebral ganglia in the anterolateral aspect of the vertebral column. These sympathetic chains lack motor or somatosensory fibers. Many of the ganglia can be blocked with local anesthetics or neurolytic agents for pain relief without significant motor effects.
Interventional therapies are geared toward interrupting or modulating the nociceptive pathways. Nerve blocks employ local anesthetics, steroids, clonidine or other adjuvants, and neurolytic agents such as alcohol or phenol to interrupt the pain signals. Radiofrequency lesioning can produce a more controlled neurolytic lesioning.
Intraspinal medication administration takes advantage of a direct application of the active agent close to the site of activity to decrease the perception of pain while minimizing the side effects. Stimulation techniques (e.g., spinal cord stimulator) use controlled electrical energy across tissue to modulate pain.
Vertebroplasty helps to relieve the compression of the vertebral body, thus decreasing the irritation of the periosteum. Neurosurgical techniques such as dorsal rhizotomy, anterolateral cordotomy, and cingulotomy are geared toward direct lesioning of specific areas of the pain pathway.
Whereas interventional approaches are based on the knowledge and understanding of various pain pathways to provide therapy by mediating at specific points or areas, specific pharmacologic classes of agents modulate the biochemical processes involved. For instance, cancer cells have high levels of cyclooxygenase (COX) isoenzymes, leading to high levels of prostaglandin. Prostaglandins are known to sensitize or directly excite nociceptors by directly binding to several prostanoid receptors expressed by nociceptors. Chronic inhibition of COX-2 has also been associated with reduced osteoclastic activity, bone resorption, and tumor burden. Thus, nonsteroidal anti-inflammatory drugs (NSAIDs) can partially attenuate cancer pain, although they are not suitable for extended use because of their side effect profile.
The analgesic effects of opioids are the result of pre- and postsynaptic modulation. Opioid binding to the presynaptic terminals leads to suppression of voltage-gated calcium channels and to inhibition of the release of substance P and calcitonin gene–related peptide. 16 At the postsynaptic terminals, opioids cause inhibition of adenylyl cyclase and activation of the inwardly rectifying potassium currents, resulting in hyperpolarization of the neurons. 17 The exact mechanism of effectiveness of acupuncture is unclear, but it may lead to the production of increased levels of endorphins. Acupuncture can be effective in relieving pain and chemotherapy-induced nausea.
Clonidine is an α 2 -adrenergic receptor agonist that modulates pain primarily by binding to the α 2A -receptor. On the presynaptic receptors, clonidine binding results in decreased release of the neurotransmitters of the primary afferent neurons involved in relaying pain signals. Clonidine binding on the postsynaptic neurons also causes hyperpolarization by increasing potassium conductance through the Gi-coupled channels. Clonidine also activates spinal cholinergic neurons, potentiating their analgesic effects. 18
Ziconotide is a synthetic neuroactive peptide that works by blocking the voltage-sensitive N -type calcium channel in the superficial dorsal horn of the spinal cord.
Endothelin antagonists also hold promise for attenuating cancer pain. Endothelins (1, 2, and 3) are a family of vasoactive peptides expressed at high levels by several types of tumors. Endothelins may contribute to cancer pain by directly sensitizing or exciting the nociceptors. 19 High plasma endothelin levels have been clinically correlated with pain severity in patients with prostate cancer. 20


WHO Analgesic Ladder
The mainstay of pain control in patients with cancer rests with oral medications, and this may be done by following established guidelines, 21 - 23 with the goal of providing pain relief with minimal side effects. Although most cancer pain can be treated satisfactorily with the conventional three-step WHO ladder approach, about 10% to 20% of such patients will require invasive interventions, 24 leading to the proposal for the fourth (interventional) step. 25, 26 The guidelines published by the American Society of Anesthesiologists 27 focused more on regional anesthetic techniques.
One of the simplest but most profound aspects of cancer pain management is the utilization of the three-step ladder recommendation. This is relatively inexpensive, may be utilized in rural or urban areas, in the hospital or the home setting in all countries, and is effective in managing 75% to 80% of patients with cancer pain. 28
Step 1: Mild pain is treated with first-line analgesics and adjuvants. These drugs include acetaminophen, NSAIDs (including COX-2 inhibitors), anticonvulsants, antidepressants, and antiarrhythmic drugs.
Step 2: For moderate cancer pain or for when the drugs used in step 1 are ineffective. This step uses weak opioids (now known as opioids for mild-moderate pain), which are used in addition to step 1 agents. Drugs include tramadol, codeine, or hydrocodone, which may be added to the drugs in step 1.
Step 3: Moderate to severe pain is treated with strong opioids, which may be supplemented with agents from steps 1 and 2. Morphine is the prototype of the strong opioids. Other strong opioids include hydromorphone, methadone, oxymorphone, and fentanyl.
Some essential principles are applicable when the WHO three-step ladder recommendation is applied. Therapy should be
1. By the mouth.
2. By the clock.
3. By the ladder.
4. Individualized.
5. Monitored with regular pain assessment and reassessment.
Thus, these drugs should be administered orally whenever possible, and the administration should be on a fixed schedule, not on an as-needed basis, along the guidelines of the WHO three-step ladder recommendation. The WHO three-step ladder has been criticized for not giving a prominent place to agents for the management of treatment-related adverse effects such as constipation. Also, a number of patients may need more specialized therapies such as patient-controlled analgesia (PCA) or interventional options such as nerve blocks or catheter placement for adequate pain control. Furthermore, in some patients who present with severe pain, it may not be appropriate to follow the various steps of the ladder. More recent guidelines 23 have, therefore, placed emphasis on flexibility, the possibility of skipping steps, and the ability to select specific drugs for specific patients. Attention to titration, individualization of therapy, analgesic polypharmacy, and ongoing management of side effects will help to strike the appropriate balance between analgesia and adverse effects. Some agent-specific information worth noting is discussed later.
Acetaminophen has minimal anti-inflammatory effects and may inhibit COX-3 (which has uncertain significance). In addition, its lack of gastrointestinal irritation and platelet toxicity may be clinically useful in selected patients. The maximum recommended dose is 4 g per day. Its lack of anti-inflammatory effects may make it less useful by itself for bone pain.
The selective COX-2 inhibitors cause less gastrointestinal irritation in comparison to the regular (traditional) NSAIDs. They are also devoid of platelet toxicity. Adverse cardiovascular effects (thromboses) are important and should be taken into consideration. COX-2–selective inhibitors may be a first-line medication in medically frail or elderly patients at risk for significant gastrointestinal hemorrhage. Celecoxib may be given as 200 mg daily, with a maximum daily dose of 600 mg. Meloxicam belongs to the regular NSAIDs, but it is COX-2 preferential at lower doses.
Tramadol is a weak opioid receptor agonist that also inhibits reuptake of norepinephrine and serotonin. It can be useful in patients with neuropathic pain. There is an increased seizure risk, especially when coadministered with drugs that lower the seizure threshold. The maximum recommended daily dose is 400 mg (300 mg for patients >75 yr). Tramadol is also available in extended-release form and in combination with acetaminophen.
Opioids have been available throughout recorded history and have been used to assuage pain and suffering. 29 Morphine was isolated from opium in the early part of the 19th century, and today, it still remains the “gold standard” for managing severe pain. It is available in several formulations and can be administered through several routes.
Meperidine is metabolized to normeperidine, which may accumulate and cause central nervous system excitation, especially in patients with renal insufficiency or on prolonged high doses. Meperidine should be considered a second-line opioid medication in patients with terminal cancer.
Methadone is an opioid with N -methyl- D -aspartate (NMDA)–receptor blocking effects. As such, it can be very useful in patients with a neuropathic component to their pain. However, methadone has a long and variable half-life and can be difficult to titrate, especially in the terminal stages of life when changes in metabolic functions are common.
The common side effects of most opioids consist of
1. Constipation
2. Nausea and vomiting.
3. Early- and late-onset respiratory depression.
4. Sedation.
5. Pruritus.
6. Urinary retention.
7. Myoclonus.
8. Seizure.
9. Hallucinations and confusion.
10. Sleep disturbance.
11. Tolerance and physical dependence.
These have been well described in the literature. Recently, more attention has focused on opioid-induced hyperalgesia, sexual dysfunction, and inappropriate antidiuretic hormone secretion.
Ample research and clinical evidence support the applicability of anticonvulsants in the management of neuropathic pain, especially in combination with opioids. 30 Gabapentin is a derivative of γ-aminobutyric acid (GABA) but is an agonist at the α 2 δ-subunit of the calcium channel. Pregabalin is similar to gabapentin but has higher absorption and higher bioavailability and may have fewer side effects. Its dosing regime is simpler than that of gabapentin.
The tricyclic antidepressants have proven analgesic effects in patients with neuropathic pain and can be particularly useful in such patients who may also have depression or insomnia. Newer antidepressants tend to have a better side effect profile but have not been as well studied as the tricyclic antidepressants for analgesia.
Corticosteroids reduce inflammation and pain. They are helpful in pain from infiltration of neural structures, bone pain, and pain in patients with advanced disease
Baclofen produces increases in the inhibitory action of GABA and is helpful in neuropathic pain. Octreotide relieves the pain of bowel obstruction. Lidocaine, in the form of Lidoderm patches, can be very helpful with certain local pain when applied over intact skin.
Other adjuvant analgesics target specific agents in the pathogenesis of pain. Osteoclasts play an essential role in cancer induced bone loss and contribute to the etiology of cancer pain. Bisphosphonates are a class of antiresorptive compounds that induce osteoclast apoptosis and can reduce pain in patients with skeletal metastasis. 31 Because of their high affinity for calcium ions, bisphosphonates target the mineralized matrix of bone. Clinical studies show that ibandronate can induce long-lasting relief of bone cancer pain. 32 Osteoprotegerins (OPGs) also hold promise for future treatment of bone pain. OPG, also known as osteoclastogenesis inhibitory factor , is a cytokine and a member of the tumor necrosis factor receptor superfamily. As secretory decoy receptors, these agents prevent the activation and proliferation of osteoclasts, thus inhibiting tumor-induced bone destruction. Calcitonin can also be helpful in refractory pain and neuropathic pain. Radiopharmaceuticals such as strontium-89 can be helpful for refractory bone pain, and when effective, the effect can last for months.

Routes of Administration
In situations in which opioids may not be administered orally, alternate routes of administration should be considered.

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