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2. Acute Pain ManagementThis textbook is written as a comprehensive overview of acute Association. Dr. de Leon-Casasola has authored or coauthoredpain management. It is designed to guide clinicians through the 115 journal articles, abstracts, and book chapters. He serves as animpressive array of different options available to them and toassociate editor for the Latin American Journal of Pain, the Argen-patients. Since the late 1990s, there has been a urry of interest in tinian Journal of Anesthesiology, the Journal of the Spanish Societythe extent to which acute pain can become chronic pain and howof Pain, and the Clinical Journal of Pain. He also is editor-in-chiefwe might reduce the incidence of such chronicity. This overview of Techniques in Regional Anesthesia and Pain Management andcovers topics related to a wide range of treatments for pain man- was listed as an exceptional practitioner by Good Housekeepingagement, including the anatomy of pain pathways, the pathophy-magazine in 2003.siology of severe pain, pain assessment, therapeutic guidelines,analgesic options, organization of pain services, and the role of Dr. Brian Ginsberg is Professor of Anesthesiology and Medicalanesthesiologists, surgeons, pharmacists, and nurses in provid- Director of the Division of Acute Pain Therapy in the Depart-ing optimal care. It also discusses the use of patient-controlled ment of Anesthesiology of Duke University School of Medicine.analgesia and how this may or may not be effective and useful.Dr. Eugene R. Viscusi is Director of Acute Pain ManagementDr. Raymond S. Sinatra currently serves as Professor of Anes- and Regional Anesthesia in the Department of Anesthesiology atthesiology at Yale University School of Medicine. He received Thomas Jefferson University in Philadelphia, Pennsylvania, andhis MD as well as a PhD in neuroscience at SUNY Downstate Associate Professor of Anesthesiology. After receiving a medicalSchool of Medicine and completed his anesthesiology residency degree from Jefferson Medical College, Dr. Viscusi completed aat the Brigham & Womens Hospital, Harvard Medical School.residency in anesthesiology at the University of Pennsylvania inDr. Sinatra joined the faculty at Yale in 1985 and organized one of Philadelphia. His research interests include the development ofthe rst anesthesiology-based pain management services in the new pain management techniques, outcome studies with painUnited States. In addition to directing the service, he has servedmanagement, and the development of novel agents and deliveryas principal investigator for dozens of clinical protocols evaluat- systems for pain management. He developed a novel nurse-ing novel analgesics and analgesic delivery systems. Dr. Sinatradriven model for delivering acute pain management with spe-has authored more than 130 scientic papers, review articles, and cially trained nurses that has served as a model for other institu-textbook chapters on pain management and obstetrical anaes- tions. Dr. Viscusi also has been a primary investigator for manythesiology and was senior editor of an earlier textbook titledemerging technologies in the perioperative arena.Acute Pain: Mechanisms and Management. Dr. Sinatra annuallyDr. Viscusi is a member of numerous professional associa-presents papers and lectures at both national and international tions, including the American Society of Anesthesiologists, themeetings and serves as a reviewer for several anaesthesiology and American Society of Regional Anesthesiology, and the Inter-pain management journals. national Anesthesia Research Society and serves on numeroussociety committees. Dr. Viscusi has lectured extensively bothDr. Oscar A. de Leon-Casasola is Professor of Anesthesiology andnationally and internationally, has authored more than 100 bookChief of Pain Medicine in the Department of Anesthesiology of chapters and abstracts, and has authored more than 50 peer-the Roswell Park Cancer Institute. His research interests include reviewed articles in journals including Journal of the Americanadvances in analgesic therapy, physiology and pharmacology of Medical Association, Anesthesiology, Anesthesia & Analgesia, andepidural opioids, perioperative surgical outcomes, thoracic and Regional Anesthesia and Pain Medicine. Dr. Viscusi currentlycardiac anesthesia, acute pain control, and chronic cancer pain.serves on the editorial board of the Clinical Journal of Pain andHe is a member of the American Society of Regional Anesthesia,regularly reviews for many journals. He also has appeared in arti-American Society of Anesthesiologists, New York State Society cles in major media including, Newsweek, the Wall Street Journal,of Anesthesiologists, American Pain Society, and Eastern Pain USA Today, and has appeared nationally on televised interviews. 3. Acute PainManagementEdited by Raymond S. Sinatra Yale UniversityOscar A. de Leon-CasasolaRoswell Park Cancer Institute Brian GinsbergDuke UniversityEugene R. ViscusiThomas Jefferson UniversityForeword Henry McQuay 4. CAMBRIDGE UNIVERSITY PRESSCambridge, New York, Melbourne, Madrid, Cape Town, Singapore, So PauloCambridge University PressThe Edinburgh Building, Cambridge CB2 8RU, UKPublished in the United States of America by Cambridge University Press, New Yorkwww.cambridge.orgInformation on this title: www.cambridge.org/9780521874915 Raymond S. Sinatra, Oscar A. de Leon-Casasola, Brian Ginsberg, Eugene R. Viscusi2009This publication is in copyright. Subject to statutory exception and to theprovision of relevant collective licensing agreements, no reproduction of any partmay take place without the written permission of Cambridge University Press.First published in print format 2009ISBN-13978-0-511-51806-5 eBook (NetLibrary)ISBN-13978-0-521-87491-5 hardbackCambridge University Press has no responsibility for the persistence or accuracyof urls for external or third-party internet websites referred to in this publication,and does not guarantee that any content on such websites is, or will remain,accurate or appropriate.Every effort has been made in preparing this book to provide accurate and up-to-date information that is in accord with accepted standards and practice at the timeof publication. Although case histories are drawn from actual cases, every efforthas been made to disguise the identities of the individuals involved. Nevertheless,the authors, editors, and publishers can make no warranties that the informationcontained herein is totally free fromerror, not least because clinical standards areconstantly changing through research and regulation. The authors, editors, andpublishers therefore disclaim all liability for direct or consequential damagesresulting from the use of material contained in this book. Readers are stronglyadvised to pay careful attention to information provided by the manufacturer ofany drugs or equipment that they plan to use. 5. ContentsContributors viiSECTION II: CLINICAL ANALGESIAAcknowledgmentsxiii 11. Qualitative and Quantitative Assessment of Pain 147Foreword: Historical Perspective, Unmet Needs, andCynthia M. Welchek, Lisa Mastrangelo,Incidence xvRaymond S. Sinatra, and Richard MartinezHenry McQuay12. The Role of Preventive Multimodal Analgesia andImpact on Patient Outcome 172SECTION I: PAIN PHYSIOLOGY AND PHARMACOLOGY Scott S. Reuben and Asokumar Buvanendran1. Pain Pathways and Acute Pain Processing 313. Oral and Parenteral Opioid Analgesics for Acute Nalini Vadivelu, Christian J. Whitney, and Pain Management 188 Raymond S. Sinatra Raymond S. Sinatra2. Pathophysiology of Acute Pain 21 14. Intravenous Patient-Controlled Analgesia204 M. Khurram Ghori, Yu-Fan (Robert) Zhang, and Pamela E. Macintyre and Raymond S. Sinatra Julia Coldrey3. Patient Variables Inuencing Acute Pain15. Clinical Applications of Epidural Analgesia 221 Management 33Daniel B. Maalouf and Spencer S. Liu Joshua Wellington and Yuan-Yi Chia16. Neuraxial Analgesia with Hydromorphone,4. Acute Pain: A Psychosocial Perspective41 Morphine, and Fentanyl: Dosing and Safety Francis J. Keefe Guidelines230Susan Dabu-Bondoc, Samantha A. Franco, and5. Nonsteroidal Anti-Inammatory Drugs andRaymond S. Sinatra Acetaminophen: Pharmacology for the Future 53 Jon McCormack and Ian Power17. Regional Anesthesia 245James Benonis, Jennifer Fortney, David Hardman, and6. Local Anesthetics in Regional Anesthesia and AcuteGavin Martin Pain Management70 John Butterworth 18. Regional Anesthesia for Acute Pain Management inthe Outpatient Setting2877. Pharmacology of Novel Non-NSAID Analgesics 82Holly Evans, Karen C. Nielsen, Marcy S. Tucker, and P. M. Lavandhomme and M. F. De KockStephen M. Klein8. Pharmacokinetics of Epidural Opioids10219. Patient-Controlled Analgesia Devices and Analgesic Bradley Urie and Oscar A. de Leon-CasasolaInfusion Pumps3029. Transitions from Acute to Chronic Pain109Benjamin Sherman, Ikay Enu, and Frederick M. Perkins Raymond S. Sinatra10. Molecular Basis and Clinical Implications of Opioid 20. Novel Analgesic Drug Delivery Systems for AcuteTolerance and Opioid-Induced Hyperalgesia114Pain Management 323Larry F. Chu, David Clark, and Martin S. AngstJames W. Heitz and Eugene R. Viscusiv 6. viContents21. Nonselective Nonsteroidal Anti-Inammatory33. Acute Pain Management in Sickle Cell DiseaseDrugs, COX-2 Inhibitors, and Acetaminophen in Patients550Acute Perioperative Pain 332Jaya L. Varadarajan and Steven J. WeismanJonathan S. Jahr, Ko N. Donkor, and34. Acute Pain Management in Patients with OpioidRaymond S. SinatraDependence and Substance Abuse56422. Perioperative Ketamine for Better Postoperative Sukanya Mitra and Raymond S. SinatraPain Outcome 366Manzo SuzukiSECTION IV: SPECIALIST MANAGED PAIN23. Clinical Application of Glucocorticoids,35. Pain Management Following Colectomy:Antineuropathics, and Other Analgesic Adjuvants A Surgeons Perspective 583for Acute Pain Management377Theodore J. SaclaridesJohan Raeder and Vegard Dahl36. Acute Pain Management in the Emergency24. Nonpharmacological Approaches for Acute PainDepartment589Management 391Knox H. Todd and James R. MinerStefan Erceg and Keun Sam Chung37. The Nurses Perspective on Acute Pain25. Opioid-Related Adverse Effects and TreatmentManagement597Options406Chris Pasero, Nancy Eksterowicz, andKok-Yuen Ho and Tong J. Gan Margo McCaffery26. Respiratory Depression: Incidence, Diagnosis, and 38. Role of the Pharmacist in Acute PainTreatment416Management607Dermot R. FitzgibbonLeslie N. SchechterSECTION III: ACUTE PAIN MANAGEMENT IN SPECIAL SECTION V: PAIN MANAGEMENT AND PATIENTPATIENT POPULATIONS OUTCOMES27. The Acute Pain Management Service: Organization 39. Economics and Costs: A Primer for Acute Painand Implementation Issues433Management Specialists623Paul Willoughby Amr E. Abouleish and Govindaraj Ranganathan28. Acute Pain Management in the Community40. Evidence-Based Medicine 630Hospital Setting 455Tee Yong Tan and Stephan A. SchugBrian E. Harrington and Joseph Marino41. Effect of Epidural Analgesia on Postoperative29. Ambulatory Surgical Pain: Economic Aspects andOutcomes637Optimal Analgesic Management 476Marie N. Hanna, Spencer S. Liu, andTariq M. Malik and Raymond S. Sinatra Christopher L. Wu30. Pediatric Acute Pain Management48742. Research in Acute Pain Management 646Giorgio Ivani, Valeria Mossetti, and Simona ItalianoCraig T. Hartrick and Garen Manvelian31. Acute Pain Management for Elderly High-Risk and 43. Quality Improvement Approaches in Acute PainCognitively Impaired Patients: Rationale forManagement655Regional Analgesia 514Christine MiaskowskiThomas M. Halaszynski, Nousheh Saidi, and44. The Future of Acute Pain Management 670Javier LopezBrian Durkin and Peter S. A. Glass32. Postcesarean Analgesia 537Kate Miller and Ferne BravemanIndex 679 7. ContributorsChapter 1 Chapter 3Nalini Vadivelu, MD Joshua Wellington, MD, MSCA-3 Resident in Anesthesiology Assistant Professor of Clinical Anesthesia and PhysicalDepartment of AnesthesiologyMedicine and RehabilitationYale University School of MedicineDepartment of AnesthesiaNew Haven, CT Indiana University Medical CenterIndianapolis, INChristian J. Whitney, MD Associate Professor of Anesthesiology Department of Anesthesiology Yuan-Yi Chia, MD Yale University School of MedicineAssociate Professor of Anesthesiology New Haven, CT Kaohsiung Veterans General Hospital National Yang-Ming University, School of Medicine, andRaymond S. Sinatra, MD, PhD Institute of Health Care Management Professor of Anesthesiology National Sun Yatsen University Director of Acute Pain Management Service Kaohsiung, Taiwan Department of Anesthesiology Yale University School of MedicineChapter 4 New Haven, CTFrancis J. Keefe, PhDChapter 2Pain Prevention and Treatment Research Program Duke University Medical CenterM. Khurram Ghori, MD Durham, NC Assistant Professor of Anesthesiology Department of Anesthesiology Yale University School of Medicine Chapter 5 New Haven, CTJon McCormack, MBChB, FRCA, MRCPYu-Fan (Robert) Zhang, MD Clinical and Surgical Sciences Anaesthesia CA-3 Resident in AnesthesiologyCritical Care and Pain Medicine Department of Anesthesiology University of Edinburgh Yale University School of Medicine Royal Inrmary Little France New Haven, CTEdinburgh, UKRaymond S. Sinatra, MD, PhD Ian Power, MD Professor of AnesthesiologyClinical and Surgical Sciences Anaesthesia Director of Acute Pain Management ServiceCritical Care and Pain Medicine Department of Anesthesiology University of Edinburgh Yale University School of Medicine Royal Inrmary Little France New Haven, CTEdinburgh, UKvii 8. viiiContributorsChapter 6 Chapter 11John Butterworth, MDCynthia M. Welchek, RPh, MS Robert K. Stoelting Professor and ChairmanClinical Pharmacist Department of AnesthesiaDepartment of Pharmacy Service Indiana University School of Medicine Yale New Haven Hospital Indianapolis, INNew Haven, CTChapter 7 Lisa Mastrangelo, RN, BC, MSNurse CoordinatorP. M. Lavandhomme, MD, PhD Acute Pain Management ServiceDepartment of AnesthesiologyDepartment of AnesthesiologySt Luc Hospital Yale University School of MedicineUniversit Catholique de Louvaine New Haven, CTBrussels, BelgiumRaymond S. Sinatra, MD, PhDM. F. De Kock, MD, PhD Professor of Anesthesiology Department of AnesthesiologyDirector of Acute Pain Management Service St Luc Hospital Department of Anesthesiology Universit Catholique de Louvain e Yale University School of Medicine Brussels, Belgium New Haven, CTRichard Martinez, MDChapter 8CA-3 Resident in AnesthesiologyBradley Urie, MD Department of Anesthesiology Fellow, Pain Management Yale University School of Medicine Department of AnesthesiologyNew Haven, CT University at Buffalo, School of Medicine Buffalo, NYChapter 12Scott S. Reuben, MDOscar A. de Leon-Casasola, MDDirector of Acute Pain Service Professor and Vice-Chair for Clinical Affairs Department of Anesthesiology Department of AnesthesiologyBaystate Medical Center University at Buffalo, School of Medicine Springeld, MA Chief, Pain Medicine and Professor of Oncology and Roswell Park Cancer Institute Buffalo, NY Professor of Anesthesiology and Pain Medicine Tufts University School of MedicineChapter 9Boston, MAFrederick M. Perkins, MDAsokumar Buvanendran, MD Chief of Anesthesia Associate Professor of Anesthesiology Veterans Administration Medical CenterDepartment of Anesthesiology White River Junction, VTDirector of Orthopedic Anesthesia Rush University Medical CenterChapter 10 Chicago, ILLarry F. Chu, MD, MS (BCHM), MS (Epidemiology)Chapter 13 Assistant Professor Department of Anesthesia Raymond S. Sinatra, MD, PhD Stanford University School of MedicineProfessor of Anesthesiology Palo Alto, CA Director of Acute Pain Management Service Department of AnesthesiologyDavid Clark, MD, PhD Yale University School of Medicine Professor New Haven, CT Department of Anesthesia and PainChapter 14 Management Veterans Affairs Palo Alto Health Care SystemPamela E. Macintyre, BMedSc, MBBS, MHA, FANZCA, Palo Alto, CAFFPMANZCA Director of Acute Pain ServiceMartin S. Angst, MDConsultant Anaesthetist Associate Professor Department of Anaesthesia, Pain Medicine and Hyperbaric Department of AnesthesiaMedicine Stanford University School of MedicineRoyal Adelaide Hospital and University of Adelaide Palo Alto, CA Adelaide, Australia 9. ContributorsixJulia Coldrey, MBBS(Hons), FANZCADavid Hardman, MDConsultant Anaesthetist Assistant Professor of AnesthesiologyDepartment of Anaesthesia, Pain Medicine and Hyperbaric Division of Orthopedic, Plastic and RegionalMedicineAnesthesiaRoyal Adelaide Hospital and University of AdelaideDepartment of AnesthesiologyAdelaide, Australia Duke University Health SystemDurham, NCChapter 15Daniel B. Maalouf, MD, MPH Gavin Martin, MB, ChB, FRCA Instructor in Anesthesiology Associate Professor of Anesthesiology Department of Anesthesia Division of Orthopedic, Plastic and Regional Hospital for Special SurgeryAnesthesia The Weill Medical College of Cornell UniversityDepartment of Anesthesiology New York, NY Duke University Health SystemDurham, NCSpencer S. Liu, MD Clinical Professor of Anesthesiology, Director of Acute PainChapter 18 Service Department of AnesthesiaHolly Evans, MD, FRCPC Hospital for Special Surgery Assistant Professor The Weill Medical College of Cornell UniversityDepartment of Anesthesiology New York, NY University of OttawaOttawa, Ontario, CanadaChapter 16 Karen C. Nielsen, MDSusan Dabu-Bondoc, MDAssistant Professor Assistant Professor of AnesthesiologyDivision of Ambulatory Anesthesiology Department of AnesthesiologyDepartment of Anesthesiology Yale University School of MedicineDuke University Medical Center New Haven, CTDurham, NCSamantha A. Franco, MD CA-3 Resident in Anesthesiology Marcy S. Tucker, MD, PhD Department of Anesthesiology Assistant Professor Yale University School of Medicine Division of Ambulatory Anesthesiology New Haven, CTDepartment of AnesthesiologyDuke University Medical CenterRaymond S. Sinatra, MD, PhD Durham, NC Professor of Anesthesiology Director of Acute Pain Management Service Stephen M. Klein, MD Department of AnesthesiologyAssociate Professor Yale University School of MedicineDepartment of Anesthesiology New Haven, CT Duke University Medical Center Durham, NCChapter 17James Benonis, MDChapter 19 Assistant Professor of Anesthesiology Division of Orthopedic, Plastic and RegionalBenjamin Sherman, MD Anesthesia CA-3 Resident in Anesthesiology Department of Anesthesiology Department of Anesthesiology Duke University Health SystemAcute Pain Management Section Durham, NC Yale University School of MedicineNew Haven, CTJennifer Fortney, MD Assistant Professor of Anesthesiology Ikay Enu, MD Division of Orthopedic, Plastic and RegionalCA-3 Resident in AnesthesiologyAnesthesia Department of Anesthesiology Department of AnesthesiologyAcute Pain Management Section Duke University Health System Yale University School of Medicine Durham, NCNew Haven, CT 10. x ContributorsRaymond S. Sinatra, MD, PhD Chapter 24 Professor of AnesthesiologyStefan Erceg, MD Director of Acute Pain Management ServiceCA-3 Resident in Anesthesiology Department of AnesthesiologyDepartment of Anesthesiology Yale University School of MedicinePain Management Service New Haven, CTYale University School of MedicineNew Haven, CTChapter 20James W. Heitz, MDKeun Sam Chung, MD Assistant Professor of Anesthesiology and MedicineAssociate Professor of Anesthesiology Jefferson Medical College Department of Anesthesiology Thomas Jefferson University Pain Management Service Philadelphia, PAYale University School of Medicine New Haven, CTEugene R. Viscusi, MD Jefferson Medical CollegeChapter 25 Thomas Jefferson UniversityKok-Yuen Ho, MBBS, MMed, FIPP, DAAPM Philadelphia, PA Department of Anaesthesia and Surgical IntensiveChapter 21 Care Singapore General HospitalJonathan S. Jahr, MD Singapore, Singapore Professor of Clinical Anesthesiology David Geffen School of Medicine at UCLATong J. Gan, MB, FRCA, FFARCSI Los Angeles, CA Department of Anesthesiology Duke University Medical CenterKo N. Donkor, PharmDDurham, NC Staff Pharmacist Department of Pharmaceutical ServicesChapter 26 UCLA Medical Center Los Angeles, CADermot R. Fitzgibbon, MD Associate Professor of AnesthesiologyRaymond S. Sinatra, MD, PhDAdjunct Associate Professor of Medicine Professor of Anesthesiology University of Washington School of Medicine Director of Acute Pain Management Section Seattle, WA Department of Anesthesiology Yale University School of Medicine Chapter 27 New Haven, CTPaul Willoughby, MDChapter 22 Associate Professor Department of AnesthesiologyManzo Suzuki, MD Stony Brook Health Sciences CenterInstructor Stony Brook, NYDepartment of AnesthesiologySecond Hospital Chapter 28Nippon Medical SchoolKanagawa, Japan Brian E. Harrington, MDStaff AnesthesiologistChapter 23Billings ClinicBillings, MTJohan Raeder, MD, PhD Professor in AnesthesiologyJoseph Marino, MD Chairman of Ambulatory Anesthesia Medical FacultyAttending Anesthesiologist University of Oslo Director of Acute Pain Management Service Ullevaal University Hospital Huntington Hospital Oslo, Norway Huntington, NYVegard Dahl, MD, PhDChapter 29 Head Department of Anaesthesia and Intensive Care Tariq M. Malik, MD Professor in AnesthesiologyAssistant Professor of Anesthesiology University of Oslo University of Chicago School of Medicine Asker and Baerum HospitalDepartment of Anesthesia and Critical Care Rud, NorwayChicago, IL 11. ContributorsxiRaymond S. Sinatra, MD, PhDChapter 33 Professor of Anesthesiology Jaya L. Varadarajan, MD Director of Acute Pain Management Service Attending Physician Department of Anesthesiology Childrens Hospital of Wisconsin Yale University School of Medicine Assistant Professor of Anesthesiology New Haven, CT Medical College of Wisconsin Milwaukee, WIChapter 30Giorgio Ivani, MDSteven J. Weisman, MD Professor Jane B. Pettit Chair in Pain Management Chairman, Department for the Ladies Staff Childrens Hospital of Wisconsin Doctors Professor of Anesthesiology and Pediatrics Department of Pediatric Anesthesiology andMedical College of Wisconsin Intensive CareMilwaukee, WI Regina Margherita Childrens Hospital Turin, ItalyChapter 34Valeria Mossetti, MD Sukanya Mitra, MDDepartment of Pediatric Anesthesiology andReaderIntensive CareDepartment of Anaesthesia and Intensive CareRegina Margherita Childrens Hospital Government Medical College & HospitalTurin, ItalyChandigarh, IndiaSimona Italiano, MDRaymond S. Sinatra, MD, PhD Department of Pediatric Anesthesiology and Professor of AnesthesiologyIntensive CareDirector of Acute Pain Management Service Regina Margherita Childrens HospitalDepartment of Anesthesiology Turin, Italy Yale University School of MedicineNew Haven, CTChapter 31 Chapter 35Thomas M. Halaszynski, DMD, MD, MBA Associate Professor of Anesthesiology Theodore J. Saclarides, MD Department of Anesthesiology Professor of Surgery Yale University School of Medicine Head of the Section of Colon and Rectal Surgery New Haven, CTDepartment of General SurgeryRush University Medical CenterNousheh Saidi, MD Chicago, IL Assistant Professor of Anesthesiology Department of AnesthesiologyChapter 36 Yale University School of Medicine New Haven, CT Knox H. Todd, MD, MPHProfessor of Emergency MedicineJavier Lopez, MDAlbert Einstein College of MedicineCA-3 Resident in Anesthesiology Director of the Pain and Emergency MedicineDepartment of Anesthesiology InstituteYale University School of MedicineDepartment of Emergency MedicineNew Haven, CT Beth Israel Medical CenterNew York, NYChapter 32 James R. Miner, MD, FACEPKate Miller, MD Associate Professor of Emergency Medicine Chief Resident in Anesthesiology University of Minnesota Medical School Department of Anesthesiology Department of Emergency Medicine Yale University School of Medicine Hennepin County Medical Center New Haven, CTMinneapolis, MNFerne Braveman, MD Chapter 37 Professor Department of AnesthesiologyChris Pasero, MS, RN-BC, FAAN Yale University School of Medicine Pain Management Educator and Clinical Consultant New Haven, CTEl Dorado Hills, CA 12. xiiContributorsNancy Eksterowicz, MSN, RN-BC, APN Spencer S. Liu, MD Advanced Practice Nurse in Pain Services Clinical Professor University of Virginia Health System Department of Anesthesia Charlottesville, VAHospital for Special SurgeryThe Weill Medical College of Cornell UniversityMargo McCaffery, MS, RN-BC, FAANNew York, NY Consultant in the Care of Patients with Pain Los Angeles, CA Christopher L. Wu, MDAssociate ProfessorChapter 38Department of Anesthesiology and Critical CareLeslie N. Schechter, PharmD MedicineAdvanced Practice PharmacistThe Johns Hopkins UniversityThomas Jefferson University HospitalBaltimore, MDPhiladelphia, PA Chapter 42Chapter 39 Craig T. Hartrick, MD, DABPM, FIPPAmr E. Abouleish, MD, MBA Anesthesiology ResearchProfessor William Beaumont HospitalDepartment of AnesthesiologyRoyal Oak, MIUniversity of Texas Medical BranchGalveston, TXGaren Manvelian, MDIndependent Pharmaceutical and Biotechnology IndustryGovindaraj Ranganathan, MD, FRCA Consultant Assistant ProfessorSan Diego, CA Department of Anesthesiology University of Texas Medical BranchChapter 43 Galveston, TX Christine Miaskowski, RN, PhD, FAANProfessor and Associate Dean for Academic AffairsChapter 40Department of Physiological NursingTee Yong Tan, MBBS, M Med (Anesthesiology)University of CaliforniaDepartment of Anaesthesia San Francisco, CAAlexandra HospitalSingapore, Singapore Chapter 44 Brian Durkin, DOStephan A. Schug, MD, FANZCA, FFPMANZCA Director of Acute Pain ServiceDepartment of Anaesthesia and Pain Medicine Assistant Professor of Clinical AnesthesiologyRoyal Perth Hospital Department of AnesthesiologyPerth, Australia Stony Brook University Medical Center Stony Brook, NYChapter 41Marie N. Hanna, MD Peter S. A. Glass, MB, ChB Associate Professor Professor and Chairman Department of Anesthesiology and Critical Care Medicine Department of Anesthesiology The Johns Hopkins UniversityStony Brook University Medical Center Baltimore, MD Stony Brook, NY 13. AcknowledgmentsTo my wife Linda and daughters Kristin, Lauren, and Elizabethwho have encouraged and supported me during my academiccareer.Raymond S. SinatraTo my family for all the support throughout life.Oscar A. de Leon-CasasolaTo my wife Brenda and my children Nicki, Terri and Aaron.Thanks for your support and help. Brian GinsbergTo my children, Christina and Andrew, my wife, Beverly, and myparents who have supported me throughout my career. Eugene R. Viscusi xiii 14. Foreword: Historical Perspective, Unmet Needs, and Incidence Henry McQuayIt is a delight and an honor to be asked to write the foreword forthis surgical pain to become chronic. I have always been skep-this text on acute pain management. We have an impressive array tical that there is some psychological factor, pejoratively someof different options for acute pain management (Figure F.1),weakness, that causes some patients to have the problem andand not all of them were available in the late 1970s. others not. As an example, take a patient who had an inguinal As a simple example of the improvement in knowledge, com-herniorrhaphy 3 years ago: the procedure was performed per-pare the analgesic efcacy work of Moertel and colleagues1 with fectly and result was perfect. This year he had the other side done,that available to us now (Figure F.2). We can use these leagueand the same procedure was performed by the same surgeon.tables of relative efcacy to say with some authority how wellThe patient described very severe postoperative pain, qualita-on average the different analgesics compare. This leaves us, of tively and quantitatively quite different from the rst operation,course, with the real-world issues of, for example, how the indi- and this severe pain persisted. Something happened to causevidual patient will react, prior experience, and drug-drug inter- the pain, and one cannot invoke a psychological explanationactions.because of the perfect result the rst time. What can we do Yet, we have the continued embarrassment of surveys that about this? We still have no strong evidence that analgesia deliv-show that a substantial number of patients still endure severeered before the pain does anything radically different from thepain after their surgery or trauma. This unmet need is a mix- same analgesia given after the pain, let alone that it preemptsture of our failure to implement effective analgesic strategies and the development of this type of chronicity. It may be that unex-the inadequacy of those strategies. Acute pain teams date back to pected severe pain is a red ag, but that is not easy to spot giventhe early 1980s, and their policies and education of both patientsthe huge variations in pain intensity experienced after a givenand caregivers have made a difference. There is little excuse now procedure. But it might be something we could pursue. Teasingfor the failure to provide adequate analgesia for straightforward apart precisely what happens during surgery would be anothercases, but we need to acknowledge that there are also difcultapproach.cases. Many of the patients whose care causes problems for the The measurement of the analgesic efcacy of preemptiveteams seem, locally for us at least, to be the patients with chronicstrategies is another of the outstanding methodological issuespain problems who are already on substantial analgesic ther-in acute pain management. Our current methods allow us toapy (e.g., chronic gastrointestinal disease) or substance abusers.measure the relative change in pain intensity. If the patient has noThings the teams can do well include the education and patientpain initially, then the method is invalid. This is the conundrumadvocacy roles within the institution. Things they may struggle in measurement of the analgesic efcacy of preemptive strategies,with include changing behavior and provision of seamless care because we have no idea whether the patient would have had noacross nights and weekends. pain without the intervention. We claim that the patient had no Since the late 1990s there has been a urry of interest in the pain because of the intervention, but they may not have had anyextent to which acute pain can become chronic pain and howpain without it.we might reduce the incidence of such chronicity.A second cause of methodological angst is the use of patient- Perhaps the most important thing this foreword points outcontrolled analgesia (PCA) as an outcome measure. Many of theis the sheer scale of the problem. From the chronic pain per- current crop of studies for instance, those studying prophylac-spective, it appears now that surgery may be the most commontic antiepileptic drugs use PCA in this way and report reducedcause of nerve damage pain and should perhaps be somethingPCA opioid consumption compared with controls. Unfortu-that patients are warned about as a possibility in the consenting nately, this difference in consumption is not reported at validprocess. Mechanistically, one can ask what happens to cause equivalence in pain scores in the two groups. The control groups xv 15. xviForeword Remove RegionalPhysical Psychologicalthe cause Medicationanalgesia methods approachesof pain Surgery, Relaxation, splinting High-tech psychoprophylaxis,epiduralLow-tech hypnosisinfusion, nerve blocks, locallocalanaesthetic anaesthetic opioid opioidNon-opioidOpioidaspirin & otherPhysiotherapy,aspirin & other NSAIDs, NSAIDs, manipulation, TENS, Figure F.2: Relative analgesic efcacy of analgesics in postoperativeacupuncture,acetaminophen acetaminophen ice pain: number-needed-to-treat (NNT) for at least 50% pain relief over combinationscombinations6 hours compared with placebo in single-dose trials of acute pain.Figure F.1: The different options for acute pain management. practice by learning from the best and try to answer some of the important outstanding issues.commonly fail to use the PCA to lower their pain scores to theHenry McQuaysame level as is seen in the active group. Unless the pain scoresNufeld Professor of Clinical Anaestheticsare equivalent, it is very difcult to interpret the difference in University of OxfordPCA consumption. We need urgently to establish the validity ofPCA as an outcome measure. REFERENCEThe editors and the authors of this book are to be congrat-ulated on keeping academic and practical attention focused on 1.Moertel CG, Ahmann DL, Taylor WF, Schwartau N. Relief of painacute pain, because there is room to both improve our current by oral medications. JAMA. 1974;229:5559. 16. Acute Pain Management 17. SECTION IPain Physiology and Pharmacology 18. 1Pain Pathways and Acute Pain ProcessingNalini Vadivelu, Christian J. Whitney, and Raymond S. SinatraUnderstanding the anatomical pathways and neurochemical With regard to a more recent classication, pain states maymediators involved in noxious transmission and pain percep-be characterized as physiologic, inammatory (nociceptive), ortion is key to optimizing the management of acute and chronicneuropathic. Physiologic pain denes rapidly perceived nontrau-pain. The International Association for the Study of Pain denes matic discomfort of very short duration. Physiologic pain alertspain as an unpleasant sensory and emotional experience associ-the individual to the presence of a potentially injurious environ-ated with actual or potential tissue damage, or described in terms mental stimulus, such as a hot object, and initiates withdrawalof such damage. Although acute pain and associated responsesreexes that prevent or minimize tissue injury.can be unpleasant and often debilitating, they serve importantNociceptive pain is dened as noxious perception result-adaptive purposes. They identify and localize noxious stimuli, ing from cellular damage following surgical, traumatic, orinitiate withdrawal responses that limit tissue injury, inhibitdisease-related injuries. Nociceptive pain has also been termedmobility thereby enhancing wound healing, and initiate motiva- inammatory 6 because peripheral inammation and inamma-tional and affective responses that modify future behavior. Nev- tory mediators play major roles in its initiation and development.ertheless, intense and prolonged pain transmission,1 as well asIn general, the intensity of nociceptive pain is proportional toanalgesic undermedication, can increase postsurgical/traumatic the magnitude of tissue damage and release of inammatorymorbidity, delay recovery, and lead to development of chronicmediators.pain (see also Chapter 11, Transitions from acute to persistent Somatic nociceptive pain is well localized and generally fol-pain). This chapter focuses on the anatomy and neurophysiology lows a dermatomal pattern. It is usually described as sharp,of pain transmission and pain processing. Particular emphasiscrushing, or tearing in character. Visceral nociceptive painis directed to mediators and receptors responsible for noxious denes discomfort associated with peritoneal irritation as wellfacilitation, as well as to factors underlying the transition from as dilation of smooth muscle surrounding viscus or tubularacute to persistent pain.passages.7 It is generally poorly localized and nondermatomal and is described as cramping or colicky. Moderate to severe visceral pain is observed in patients presenting with bowel or ureteral obstructions, as well as peritonitis and appendicitis. Vis-C L A S S I F I C AT I O N O F PA I Nceral pain radiating in a somatic dermatomal pattern is described as referred pain. Referred pain8 may be explained by convergencePain can be categorized according to several variables, includ-of noxious input from visceral afferents activating second-ordering its duration (acute, convalescent, chronic), its pathophysio-cells that are normally responsive to somatic sensation. Becauselogic mechanisms (physiologic, nociceptive, neuropathic),2 and of convergence, pain emanating from deep visceral structuresits clinical context (eg, postsurgical, malignancy related, neu- may be perceived as well-delineated somatic discomfort at sitesropathic, degenerative). Acute pain3 follows traumatic tissueeither adjacent to or distant from internal sites of irritation orinjuries, is generally limited in duration, and is associated with injury.temporal reductions in intensity. Chronic pain4 may be dened The process of neural sensitization and the clinical termas discomfort persisting 36 months beyond the expected period hyperalgesia9 describe an exacerbation of acute nociceptive pain,of healing. In some chronic pain conditions, symptomatol-as well as discomfort in response to sensations that normallyogy, underlying disease states, and other factors may be ofwould not be perceived as painful. These changes, termed hyper-greater clinical importance than denitions based on duration of pathia10 and allodynia,11 although common following severediscomfort.5 Clinical differentiation between acute and chronicor extensive injuries, are most pronounced in patients devel-pain is outlined in Table 1.1. oping persistent and neuropathic pain. Hyperalgesia can be 3 19. 4 Nalini Vadivelu, Christian J. Whitney, and Raymond S. SinatraTable 1.1: Clinical Differentiations between Acute and Table 1.2: Characteristics of HyperalgesiaChronic PainAcute Pain Chronic PainHyperalgesia Denes a state of increased pain sensitivity and enhanced1. Usually obvious tissue damage 1. Multiple causes (malignancy, perception following acute injury that may persist chronically.benign) The hyperalgesic region may extend to dermatomes above and below2. Distinct onset2. Gradual or distinct onset. the area of injury and is associated with ipsilateral (and occasionally3. Short, well characterized 3. Persists after 36 mo of contralateral) muscular spasm/immobility. duration healing(Hyperalgesia is may be observed following incision, crush, amputation, and blunt trauma.)4. Resolves with healing 4. Can be a symptom ordiagnosis. Primary hyperalgesia5. Serves a protective function5. Serves no adaptive purpose Increased pain sensitivity at the injury site6. Effective therapy is available6. May be refractory to treatment Related to peripheral release of intracellular or humoral noxious mediators Secondary hyperalgesiaclassied into primary and secondary forms (Table 1.2). Pri-mary hyperalgesia12 reects sensitization of peripheral nocicep- Increased pain sensitivity at adjacent, uninjured sitestors and is characterized by exaggerated responses to thermalRelated to changes in excitability of spinal and supraspinal neuronsstimulation at or in regions immediately adjacent to the siteAbnormal sensations associated with hyperalgesiaof injury. Secondary hyperalgesia13 involves sensitization withinthe spinal cord and central nervous system (CNS) and includesHyperpathia (increased or exaggerated pain intensity with minor stimulation)increased reactivity to mechanical stimulation and spread of thehyperalgesic area.13 Enhanced pain sensitivity extends to unin-Allodynia (nonnoxious sensory stimulation is perceived as painful)jured regions several dermatomes above and below the initial Dysesthesia (unpleasant sensation at rest or movement)site of injury. The stimulus response associated with primaryParesthesia [unpleasant often shock-like or electrical sensationand secondary hyperalgesia is outlined in Figure 1.1.precipitated by touch or pressure (CRPS-II causalgia)] Neuropathic pain is dened by the International Associa-tion for the Study of Pain as pain initiated or caused by apathologic lesion or dysfunction in peripheral nerves and CNS.Some authorities have suggested that any chronic pain statechronic regional pain syndrome II16 describes pain followingassociated with structural remodeling or plasticity changesinjury to sensory nerves, whereas discomfort associated withshould be characterized as neuropathic.1 Disease states associ-injury or abnormal activity of sympathetic bers is termed reexated with classic neuropathic sysmptoms include infection (eg, sympathetic dystrophy or chronic regional pain syndrome I.17herpes zoster), metabolic derangements (eg, diabetic neuropa-Finally, it is well recognized that certain acute traumaticthy), toxicity (eg, chemotherapy), and Wallerian degenerationand chronic pain conditions are associated with a mixture ofsecondary to trauma or nerve compression. Neuropathic pain nociceptive and neuropathic pain. Symptoms are proportionalis usually constant and described as burning, electrical, lanci- to the extent of neural versus nonneural tissue injuries. Clinicalnating, and shooting. Differences between the pathophysiologic appreciation of the qualitative factors of the pain complaint helpsaspects of physiologic, nociceptive, and neuropathic pain areguide the caregiver in differentiating between pain categoriesoutlined in Table 1.3. (Table 1.4). A common characteristic of neuropathic pain is the paradox-ical coexistence of sensory decits in the setting of increased nox- PA I N P E RC E P T I O Nious sensation.14 By convention, symptoms related to periph-eral lesions are termed neuropathic, whereas symptoms relatedA number of theories have been formulated to explain nox-to spinal cord injuries are termed myelopathic.15 Causalgia or ious perception.18 One of the earliest ideas, termed the speci- city theory, was proposed by Descartes.19 The theory suggested that specic pain bers carry specic coding that discriminates Worst Pain between different forms of noxious and nonnoxious sensation. The intensity theory, proposed by Sydenham,20 suggested that the intensity of the peripheral stimulus determines which sen- Normalsation is perceived. More recently, Melzack and Wall21 proposed Hyperalgesiathe gate control theory and suggested that sensory bers of dif- Response fering specicity stimulate second-order spinal neurons (dorsal horn transmission cell or wide dynamic range [WDR] neuron)No PainAllodynia that, depending on their degree of facilitation or inhibition, re at varying intensity. Both large- and small-diameter afferents can activate transmission cells in dorsal horn; however, large Increasing Stimulus Intensity sensory bers also activate inhibitory substantia gelatinosa (SG) cells.22 Indeed, it is the neurons and circuitry within the sub-Figure 1.1: Stimulus response alteration observed with hyperalgesia. stantia gelatinosa that determine whether the gate is opened 20. Pain Pathways and Acute Pain Processing 5Table 1.3: Pathophysiologic Representation of PainCategoryCause Symptom ExamplesPhysiologic Brief exposure to a noxious Rapid yet brief pain perception Touching a pin or hot objectstimulusNociceptive/inammatory Somatic or visceral tissue injury Moderate to severe pain,Surgical pain, traumatic pain,with mediators having andescribed as crushing or stabbing sickle cell crisisimpact on intact nervous tissueNeuropathic Damage or dysfunction ofSevere lancinating, burning orNeuropathy, CRPS. Postherpeticperipheral nerves or CNSelectrical shock like painNeuralgiaMixed Combined somatic and nervousCombinations of symptoms; softLow back pain, back surgery paintissue injury tissue plus radicular pain within the SG, appears to be the key that unlocks the dorsal hornTable 1.4: Qualitative Aspects of Pain Perception gate, thereby facilitating pain transmission. Identifying media-1. Temporal: onset (when was it rst noticed?) and duration (eg, tors that increase or diminish spinal sensitization and help close acute, subacute, chronic) the gate will be important targets for treating pain in the near future.23 The anatomic pathways mediating pain perception are2. Variability: constant, effort dependent (incident pain), waxing and outlined in Figure 1.4. waning, episodic are3. Intensity: average pain, worst pain, least pain, pain with activity of livingTRANSDUCTION4. Topography: focal, dermatomal, diffuse, referred, supercial, deepTransduction27 denes responses of peripheral nociceptors to5. Character: sharp, aching, cramping, stabbing, burning, shooting traumatic or potentially damaging chemical, thermal, or me-6. Exacerbating/Relieving: worse at rest, with movement or nochanical stimulation. Noxious stimuli are converted into a cal- difference; incident pain is worse with movement (stretching andcium ion (Ca2+ ) mediated electrical depolarization within the tearing of injured tissue); intensity changes with touch, pressure, distal ngerlike nociceptor endings. Peripheral noxious media- temperature tors are either released from cells damaged during injury or as7. Quality of life: interfere with movement, coughing, ambulation, a result of humoral and neural responses to the injury. Cellular daily life tasks, work, etc.damage in skin, fascia, muscle, bone, and ligaments is associated with the release of intracellular hydrogen (H+ ) and potassium (K+ ) ions, as well as arachadonic acid (AA) from lysed cell membranes. Accumulations of AA stimulate and upregulate theor closed.23 Substantia gelatinosa cells close the gate by directlycyclooxygenase 2 enzyme isoform (COX-2) that converts AAsuppressing transmission cells. In contrast, increased activityinto biologically active metabolites, including prostaglandin E2in small-diameter bers decreases the suppressive effect of SG (PGE2 ), prostaglandin G2 (PGG2 ), and, later, prostaglandin H2cells and opens the gate. Peripheral nerve injuries also open(PGH2 ). Prostaglandins28 and intracellular H+ and K+ ions playthe gate by increasing small ber activity and reducing largekey roles as primary activators of peripheral nociceptors. Theyber inhibition.24 Finally, descending inhibition from higheralso initiate inammatory responses and peripheral sensitizationCNS centers and other inhibitory interneurons can also sup-that increase tissue swelling and pain at the site of injury.press transmission cells and close the gate. Some aspects ofthe gate control theory have fallen out of favor; nevertheless,pain processing in dorsal horn and, ultimately, pain perceptionare dependent on the degree of noxious stimulation, local anddescending inhibition, and responses of second-order transmis- CentralDescendingsion cells. A schematic representation of the gate control systemControlModulationis presented in Figure 1.2. Large Woolf and coworkers have proposed a new theory to explain fiberspain processing.27 They suggest that primary and secondary -hyperalgesia as well as qualitative differences among physio- ++ --logic, inammatory, and neuropathic pain reect sensitizationInputT Ascending ActionSG Systemof both peripheral nociceptors and spinal neurons (Figure 1.3). -- +Noxious perception is the result of several distinct processesthat begin in the periphery, extend up the neuraxis, and ter-Smallminate at supraspinal regions responsible for interpretationfibersand reaction. The process includes nociceptor activation, neu-Dorsal Horn Gateral conduction, spinal transmission, noxious modulation, lim-Figure 1.2: The gate control theory of pain processing. T = Second-bic and frontal-cortical perception, and spinal and supraspinalorder transmission cell; SG = substantia gelatinosa cell. (Modiedresponses. The process of central sensitization, particularlyfrom Melzack R and Wall PD, Science. 1965;150(699):971979.).21 21. 6Nalini Vadivelu, Christian J. Whitney, and Raymond S. Sinatra Low intensityHigh intensity Low intensity stimulationStimulationStimulation Low threshold mechanoreceptor Sensitized nociceptorA A and C fibersPNSPNSLow threshold High threshold A fiberA and c fiberCNS nociceptorsCNSDorsalHornCellsHyperexcitable dorsal horn neuronInnocuousBriefPain sensation Pain(a) (b)Figure 1.3: (a) The sensitization theory of pain perception suggests that brief high-intensity noxious stimulation in the absence of tissue injuryactivates the nociceptive endings of unmyelinated or thinly myelinated (high-threshold) bers, resulting in physiologic pain perception ofshort duration. Other low-threshold sensory modalities (pressure, vibration, touch) are carried by larger-caliber (low-threshold) bers. Largeand small bers make contact with second-order neurons in the dorsal horn. (b) Following tissue injuries and release of noxious mediators,peripheral nociceptors become sensitized and re repeatedly. Peripheral sensitization occurs in the presence of inammatory mediators, whichin turn increases the sensitivity of high-threshold nociceptors as well as the peripheral terminals of other sensory neurons. This increase innociceptor sensitivity, lowering of the pain threshold, and exaggerated response to painful and nonpainful stimuli is termed primary hyperalgesia.The ongoing barrage of noxious impulses sensitizes second-order transmission neurons in dorsal horn via a process termed wind-up. Centralsensitization results in secondary hyperalgesia and spread of the hyperalgesic area to nearby uninjured tissues. Inhibitory interneurons anddescending inhibitory bers modulate and suppress spinal sensitization, whereas analgesic under medication and poorly controlled pain favorssensitization. In certain settings central sensitization may then lead to neurochemical/neuroanatomical changes (plasticity), prolonged neuronaldischarge and sensitivity (long-term potentiation), and the development of chronic pain. (Modied from Woolf CJ, Salter MW. Neuronalplasticity: increasing the gain in pain. Science. 2000;288(5472):17651769.)1In addition to PGEs, leukotrienes,29 5-hydroxytryptamineLimbic Cortex (5-HT),30 bradykinin (BK),31 and histamine32 released followingtissue injury are powerful primary and secondary noxious sensi-Sensory Cortextizers. 5-hydroxytryptamine released after thermal injury sensi-tizes primary afferent neurons and produces mechanical allody-nia and thermal hyperalgesia via peripheral 5-HT2a receptors.33 Thalamus Bradykinins role in peripheral sensitization is mediated by G-protein-coupled receptors,1 B1 and B2, that are expressed by Trauma the primary nociceptors. When activated by BK and kallidin,Descending Ascendingthe receptor-G-protein complex strengthens inward Na+ ux, Pathway Pathways whereas it weakens outward K+ currents, thereby increasing Central greyNociceptornociceptor excitability. These locally released substances increase Mid Brainvascular permeability, initiate neurogenic edema, increase noci-Noxious FiberDorsal ceptor irritability, and activate adjacent nociceptor endings. TheHornresulting state of peripheral sensitization is termed primary Motor Efferenthyperalgesia.Spinal CordIn addition to locally released and humoral noxious medi-ators, neural responses play an important role in maintain-R Sinatra, 2007 ing both peripheral sensitization and primary hyperalgesia.Figure 1.4: An anatomical overview of pain pathways. NoxiousBradykinin, 5-HT, and other primary mediators stimulate ortho-information is conveyed from peripheral nociceptors to the dorsal dromic transmission in sensitized nerve endings and stimulatehorn via unmeylinated and myelinated noxious bers. Second-orderthe release of peptides and neurokinins, including calcitoninspinal neurons send impulses rostrally via two distinct pathways, the gene-related protein (CGRP),34 substance P (sP),35 and cholo-neospinothalamic and paleospinothalamic tracts. These cells also acti-cystokinin (CCK),36 in and around the site of injury. Substancevate motor and sympathetic efferents within the spinal cord. Ascend-P, via a feedback loop mechanism, enhances peripheral sensi-ing tracts make contacts in the brainstem and midbrain, central gray,tization by facilitating further release of bradykinin, histamineand thalamus. Projections are then made with the frontal and lim-bic cortex. Descending bers emanating from cortex, hypothalamus, from mast cells, and 5-HT. Calcitonin gene-related protein is aand brainstem project to the spinal cord to modulate pain trans-37-amino-acid peptide found in the peripheral and central ter-mission.minals of more than 50% of C bers and 35% of A bers.37 22. Pain Pathways and Acute Pain Processing 7 Nociceptive Ending (Primary Afferent Fiber)Noxious SoupCa++Na+ Peptides- TRPAction Potential sP, CCK, CGRPLocal &VascularMediators- TraumaticBradykinin, Mediators-Cytokines K+, H+,Histamine, PGE5HTATPTRPNeural Mediators- Ca++Epinephrine,Norepinephrine Generator PotentialR Sinatra 2007Figure 1.5: Pain is detected by unmyelinated nerve endings, termed nociceptors, that innervate skin, bone,muscle, and visceral tissues. Nociceptor activation initiates a depolarizing Ca2+ current or generatorpotential. Generator potentials depolarize the distal axonal segment and initiate an inward Na+ currentand self-propagating action potential. Following tissue injury, cellular mediators (potassium, hydrogenions, and prostaglandin released from damaged cells, as well as bradykinin [BK] released from damagedvessels) activate the terminal endings (nociceptors) of sensory afferent bers. Prostaglandin (PGE), syn-thesized by cyclooxygenase 2, is responsible for nociceptor sensitization and plays a key role in peripheralinammation. Orthodromic transmission in sensitized afferents leads to the release of peptides (sub-stance P (sP), cholycystokinin (CCK), and calcitonin gene-related peptide (CGRP) in and around the siteof injury. Substance P is responsible for further release of BK and also stimulates release of histamine frommast cells and 5HT from platelets, which further increases vascular permeability (neurogenic edema) andnociceptor irritability. The release of these mediators and others, such as serotonin (5HT) and cytokines,creates a noxious soup that exacerbates the inammatory response, recruits adjacent nociceptors, andresults in primary hyperalgesia. Reex sympathetic efferent responses may further sensitize nociceptorsby releasing noradrenaline and, indirectly, by stimulating further release of BK and sP and leading toperipheral vasoconstriction and trophic changes.Like sP, CGRP38 is produced in the cell bodies of primaryof IL-1 result in allodynia and the development of persistentnociceptors located in the dorsal root ganglion. Following axonalpain,42 whereas effective postoperative analgesia decreases proin-transport to peripheral and central terminals, these substancesammatory cytokines levels.43,44 According to Bessler et al,42initiate mechanical and thermal hyperalgesia. When releasedgenetic polymorphisms inuence production of proinamma-at peripheral endings, CGRP enhances PGE39 and histamine-tory cytokines and may contribute to observed interindividualinduced vasodilation and inammatory extravasation. It alsodifferences in postoperative pain intensity scores and variationsprolongs the effect of sP by inhibiting its peripheral metabolic in morphine consumption.breakdown.40 Finally, reex-sympathetic efferent responses also The inammatory mediators and proinammatory cyto-sensitize nociceptors by releasing norepinephrine, which pro-kines described above activate transducer molecules such as theduces peripheral vasoconstriction at the site of injury. Nore- transient receptor potential (TRP) ion channel.1 At least 8 differ-pinephrine also stimulates release of BK and sP and leads to ent TRP ion channels have been identied and respond differen-atrophic changes in bone and muscle. tially to thermal, traumatic, and chemical 14 evoked mediators Peripheral sensitization is also associated with release of within the microenvironment. The TRP-VI/capsaicin ion chan-nerve growth factor, which alters intracellular signaling path-nel has been well described. This 4-unit receptor contains aways and initiated posttranslational regulatory changes, includ- central ion channel that permits inward Ca2+ and Na+ currentsing phosphorylation of tyrosine kinase and G proteins. These following stimulation by H+ ions, heat, and direct applicationalterations markedly increase the sensitivity and excitability ofof capsaicin,45 the active chemical compound found in hot pep-distal nociceptor terminals.41 For example, nociceptors are acti-per. The inward ux of Ca2+ via TRP ion channels is respon-vated at lower temperatures (< 40 C) and in response to lower sible for the generator potential.31 Generator potentials sum-concentrations of PGE2 and other primary mediators.mate and depolarize the distal axonal segment and the resulting Acute tissue injury results in an increased synthesis and action potential is then conducted centrally to terminals in theextravasation of humoral proinammatory cytokines, such as dorsal horn. The noxious soup of local humoral and neu-interleukin- (IL) 1 and IL-6. These cytokines play an impor-ral mediators released following acute tissue injury as well astant role in exacerbating edematous and irritative componentsthe nociceptor response to peripheral injury are summarized inof inammatory pain.42 Studies have shown that elevated levels Figure 1.5. 23. 8 Nalini Vadivelu, Christian J. Whitney, and Raymond S. SinatraTable 1.5: Classication of Primary Afferent Nerve FibersCharacteristicA A C bersDiameter size LargestSmallVery smallDegree of myelination Myelinated Thinly myelinatedUnmyelinatedConduction velocity Very FastFast Slow3050 m/s525 m/s T in the ABCB1 (P-glycoprotein) gene.74With regard to pharmacodynamic variability, relationships The cytochrome P450 2D6 (CYP2D6) is known to metab-between CSF concentrations of endogenous opioids and theolize many drugs. The activity of CYP2D6 ranges from com-amount of exogenous analgesic required to maintain effectiveplete deciency to ultrafast metabolism, depending on at leastpain relief have been observed. Dahlstrom and coworkers57 16 different known alleles.75 This may account for variationfound that patients presenting with low CSF levels of -in metabolism for dextromethorphan, tramadol, and codeine,endorphin required signicantly greater amounts of PCAamong other medications.meperidine. These investigators observed a linear relationshipbetween preoperative CSF concentrations of endogenous opi-oids and postoperative PCA demand doses and total opioidPAT I E N T S W I T H H I S TO R I E S O F S U B S TA N C Edelivered.ABUSE OR OPIOID DEPENDENCIESPatients abusing heroin or diverted opioid analgesics experienceG E N E P O LY M O R P H I S M Sthe same intensity of acute postsurgical pain as nondependentindividuals. Nevertheless caregivers tend to limit opioid admin-As mentioned above, acute pain management is often compli-istration in these patients. PCA is often withheld from these indi-cated by interindividual variabilities and undesired effects of viduals, and neural blockade or epidural analgesic techniques areanalgesics. Genetic polymorphisms are thought to play a largersubstituted because self-administered IV boluses may reinforcerole than previously realized in the interindividual variability of drug-seeking behavior.39 More recent practice guidelines permitresponse to analgesics. A small, but growing, number of clinicalwell-supervised PCA therapy for use by patients having a his-trials have focused on the genes responsible for modulating the tory of alcohol, cocaine, and heroin abuse. Opioid-dependentanalgesic response to many commonly used medications. patients with a history of chronic pain and tolerance develop- A recent study revealed that women respond better to nal-ment also require increased amounts of opioids to compensatebuphine (a -opioid agonist) than to morphine (a -opioid for both baseline requirements as well as that needed to controlagonist), whereas men respond better to morphine in the post- pain following surgery (see also Chapter 34, Acute Pain Manage-operative period,58 suggesting the presence of sex-related dif- ment in Patients with Opioid Dependence and Substance Abuse.)ferences in the opioid receptor system. Another study showedthat the several single nucleotide polymorphisms (SNPs) iden-tied in the human -opioid receptor gene, with the 118A>GPAT I E N T S W I T H O R G A N I M PA I R M E N Tmutation being the most common, might be associated with theO R FA I LU R Eclinical effects of opioid analgesics.59,61 In vitro, the binding of endorphin to the receptor of aDeclines in cardiac, hepatic, and renal function are often asso-homozygous G allele has been shown to be tighter by 3-fold com- ciated with alterations in the volume of distribution, clearance,pared with its binding to a homozygous A allele.62 Moreover, aand excretion of most analgesic agents. For analgesics havingrecent report suggested that cancer patients who were homozy- high hepatic uptake and clearance, reductions in hepatic bloodgous for the G118 variant required higher doses of oral morphineow are accompanied by proportional decrements in the overallfor long-term treatment of pain.60 Romberg et al63,64 studied extraction rate and prolonged pharmacological effects.7680the pharmacokinetics and pharmacodynamics of morphine-The patient with organ compromise or failure may present6-glucuronide (M6G), a -opioid agonist, and observed thatwith unique considerations, depending on the analgesic toA118G mutation of the human -opioid receptor gene also be administered. These patients may include those who havereduced analgesic responses to M6G. This genetic variation of the renal or hepatic impairment or failure or others recovering-opioid receptor was also associated with the different response from nephrectomy and hepatic lobectomy. Analgesic efcacyof surgical pain to intravenous PCA morphine therapy. It mightmay be altered not only by impaired clearance of the med-be warranted to extend these results to other ethnic groups.65,66 ication but also through the production and potential accu-In an recent review on the evidence for genetic modulation of mulation of metabolites which may be toxic. A classic exam-analgesic response, L tsch and Geisslinger67 described that the ople is accumulation of meperidines renally cleared metabolite,118A > G mutation of the -opioid receptor affected up to normeperidine, which can precipitate CNS toxicity. A recent17% of subjects in their response to alfentanil,68 morphine,69review of the impact of concurrent renal or hepatic diseaseM6G,63,64 and levomethadone.70on the pharmacology of the patient requiring acute pain man- The polymorphism of the human catechol-O-methyl- agement found specic differences in safety of the pharmaco-transferase (COMT) gene has been found to inuence thelogical prole among pain medications.76,77 These differencesmorphine requirements in cancer pain patients.71 Dopamine,are presented in Table 3.3. According to this table, there are aepinephrine, and norepinephrine are inactivated in the ner- number of safer medications that can be used in patients withvous system by COMT. Enzyme activity of COMT may vary renal impairment as these drugs typically do not have a signi-3- to 4-fold because of a common functional polymorphismcantly prolonged clearance or deliver a high active metabolite(Val158Met). Patients with the Val/Val genotype needed more load. Other medications may be used with caution wherein 53. 38 Joshua Wellington and Yuan-Yi ChiaTable 3.3: Pharmacological Safety Prole with Renal orAs methadone has a very long half-life, it is contraindicated inHepatic Impairmentpatients with severe liver disease. Dextropropoxyphene has alsobeen implicated in several cases of hepatotoxicity.82Require PrecautionSafest(ie, dose reduction) Avoid To prevent cumulative increases in levels of analgesics,82 butmaintain therapeutic plasma concentrations, it is essential thatRenal impairment/failurethe dose of drugs that undergo hepatic biotransformation orare eliminated by the kidneys be reduced. This can be accom-Acetaminophen AmitriptylineAspirinplished by either decreasing the amount of each dose while main-AlfentanilBupivacaineDextropropoxyphene taining the normal dosing schedule or by increasing the inter-Buprenorphine ClonidineMeperidine val between doses while administering the standard size dose.FentanylGabapentin NSAIDs Dosage adjustment is of critical importance if renal function isKetamineHydromorphone less than 50% of normal and the agent to be administered is to aRemifentanilLevobupivacaine great degree (>50%) excreted unchanged or has active metabo-SufentanilLidocaine lites that are primarily eliminated by the kidney.39,7779 Patientssuffering congestive heart failure experience greater reductionsMethadonein hepatic and renal perfusion than blood ow directed to theMexilitineheart, lungs, and central nervous system. As would be expectedMorphineboth hepatic clearance/biotransformation and renal eliminationOxycodone of drug will be compromised, whereas delivery of free drug toTramadolthe nervous system and heart may be increased. Hepatic impairment/failureRemifentanilOther opioidsAmitriptylineC O N C LU S I O N CarbamazepinePatient variables clearly inuence analgesic dose requirements Dextropropoxypheneand analgesic response. Factors associated with the greatest Meperidine reduction in analgesic requirement as well as potential toxic- Valproateity include increasing patient age and hepatorenal dysfunction.Variables responsible for increased analgesic requirement andless effective pain control include opioid tolerance, more exten-dose reduction is usually necessitated. Some drugs should not sive surgery, and cultural inuences. Cognitive decits lead tobe used because of the high risk of toxicity. Although mor- reductions in both analgesic requirement as well as ineffectivephine remains primarily unaffected by renal failure, accumula-pain control. It seems likely that understanding and utilizingtion of morphine-6-glucuronide (an active metabolite that may genetic polymorphisms that mediate receptor efcacy and druginduce CNS irritability) and morphine-3-glucuronide (inactive metabolism will have clinical usefulness by either increasingmetabolite) have been reported.78 Buprenorphine may provide analgesic sensitivity or diminishing toxicity. In the near future,analgesic efcacy in patients with renal failure requiring inter- oral and intravenous analgesic dosing and selection of opti-mittent hemodialysis. Filitz and coworkers79 recently found thatmal compounds may be facilitated by presurgical analysis ofbuprenorphine and its metabolite norbuprenorphine were notgenetic markers. At present, elderly patients and those present-elevated in plasma levels in chronic pain patients with end-ing with multiorgan failure have the most to gain from advancesstage renal disease. Additionally, hemodialysis did not affectin neuraxial analgesic therapy and continuous neural block-buprenorphine plasma levels, allowing for stable analgesia. ade. Such therapy provides highly effective pain control andWhen using pain medications in the patient with hepatic reduction in stress responses to pain, whereas at the same timeimpairment, consideration must be given to the impaired clear-reducing opioid burden and the deleterious effects of opioids onance and increased oral bioavailability caused by a reduced the CNS.rst-pass metabolism. The primary metabolic pathway for mostopioids is oxidation, which may be decreased in patients withhepatic cirrhosis. Morphine and buprenorphine are exceptionsREFERENCESthat primarily undergo glucuronidation. 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Chou WY, Wang CH, Liu PH, et al. The human opioid recep- totoxicity: four cases and literature review. Therapie. 2002;57:464tor A118G polymorphism affects intravenous patient-controlled472. 56. 4 Acute Pain: A Psychosocial PerspectiveFrancis J. KeefeOur understanding of the psychosocial aspects of pain has in battleeld situations but also in civilian situations. In a studyadvanced considerably since the early 1980s. Much has beenof 138 alert and oriented patients seen in an emergency roomlearned about psychosocial factors that inuence pain and setting, Melzack et al4 found that 37% reported feeling no painpsychosocial interventions that can enhance pain control.1,2at the time of injury. Delays in the onset of pain ranged from 1Recently, there has been growing interest in applying the psy-to 9 hours. Taken together, the results of these studies suggestchosocial perspective to enhance our understanding and abilitythat the relationship between injury and pain is not as simpleto treat acute pain.and straightforward as assumed by the traditional biomedicalThis chapter focuses specically on psychosocial aspects of model.acute pain. The chapter is divided into four sections. The rst sec- Other limitations of the biomedical model include its failuretion provides a conceptual background on psychosocial aspects to account for observations such as pain that returns and persistsof acute pain. The second section highlights research on the role following neurosurgical lesions to pain pathways, variations inof psychosocial factors in acute pain. The third summarizes the pain, or pain relief following the same treatments that occurresults of recent studies testing the efcacy of psychosocial inter-in patients with very similar degrees of tissue pathology.2,5 Theventions for acute pain. The chapter concludes with a discussionbiomedical model also fails to address the effects that psychoso-of future directions for work in this important area. cial factors can have on the pain experience. Growing recognition of the limitations of the traditionalmedical model, has spurred interest in alternative theories ofC O N C E P T UA L B AC KG RO U N D pain. One of the most inuential of these theories is Melzackand Walls gate control theory.6 The basic tenet of this theory isTraditionally, acute pain has been understood using a biomedicalthat there is a gating mechanism in the dorsal horn of the spinalmodel.2 According to this model, acute pain is a warning signal cord that inuences the transmission of noxious input from thethat results from nociceptive input as a result of tissue damageperiphery to the brain. Important from a psychosocial perspec-or injury. In the biomedical approach, careful assessments aretive is the notion that the action of the spinal gating mechanismconducted to identify sources of tissue damage or injury that are is inuenced, not only by peripheral input (ie, relative balancecausing pain. Medical and/or surgical interventions designed to of large diameter and small diameter ber input), but also bycorrect or ameliorate underlying tissue damage or injury aredescending input from higher brain centers. The gate controlthen carried out to eliminate or reduce pain.2 In the biomedicaltheory proposes that, under certain circumstances (eg, exposuremodel, psychosocial factors play a secondary role in that theyto danger, use of adaptive coping skills, or high levels of socialare viewed simply as responses to pain itself.support), neural processes in the brain can be activated in a wayAlthough the biomedical model has been very inuentialthat closes the gate in the spinal cord and inhibits transmissionin understanding and treating acute pain, its limitations haveof noxious signals to the brain. Under other circumstances (eg,become increasingly clear since the late 1950s.2 One problemwhen preoccupied with pain, depressed, or exposed to ongoingwith this model is that acute pain is not always proportional tointerpersonal stress), neural processes in the brain can be acti-the amount of tissue damage or injury. A classic study conductedvated in a way that opens the gate and facilitates transmission ofby Beecher3 at the Anzio beachhead found that 66% of woundednoxious signals to the brain. The gate control theory thus under-soldiers reported feeling no pain. Beecher reasoned that a psy- scores that, through its inuence on spinal gating mechanisms,chological factor (e, the expectation that the wound would result the brain plays a crucial role in pain inhibition and facilitation.in removal from the battleeld to a safe setting) tempered the The gate control theory was important because it provided aexperience of pain. Pain-free injuries have been noted not only way of integrating psychosocial variables into our understanding 41 57. 42 Francis J. Keefeand treatment of pain. In contrast to the traditional biomedical P S YC H O S O C I A L FAC TO R S A N D AC U T E PA I Nmodel, the gate control theory did not view psychosocial factorsas simply responses to pain but rather as an integral componentConverging lines of evidence suggest that psychosocial factorsof pain processing.5 The gate control theory not only stimulated play an important role in the experience of acute pain. In thislaboratory and clinical research on the psychology of pain, it alsosection, we consider four psychosocial factors that are amongled to heightened interest in the role that psychological interven-the most intensively studied in the context of acute clinical pain:tions might play in managing acute and persistent clinical pain.1anxiety, pain-related anxiety and fear, pain catastrophizing, and More recently, Melzack5,7 has proposed the neuromatrixthe social context.theory of pain, a theory that builds on and extends conceptsintroduced in the gate control theory. Melzack had studied per- Anxietysons with total spinal sections who experienced phantom bodypains (ie, pains that persisted despite a lack of clear-cut periph-Pain can be inuenced by and, in turn, inuence negative affecteral tissue pathology).5 To account for such phenomena, he (eg, anxiety, depression, and anger).1 Of the negative affects asso-proposed that pain is produced by a body-self neuromatrix, ciated with acute pain, there is growing evidence that anxiety isreecting input from a network of widely distributed brain neu-the most important. Feeney,8 for example, conducted a cross-rons. The neuromatrix consists of a network made up of neu-sectional study examining the relationship of negative affectrons that loop between the thalamus and the cortex and the to acute pain in older adults. Participants in this study werecortex and limbic systems. The neuromatrix theory states that100 older patients (mean age = 79 years) who were recentlythe composition of the neuromatrix is initially determined by(within 5 days) admitted to a rehabilitation unit after ortho-genetic background, but that it is subsequently modied by a pedic surgery (e.g., hip or knee replacements). All participantspersons sensory experiences. Although this theory recognizescompleted a measure of pain along with ve measures of nega-sensory input as an important factor inuencing pain, it main- tive affect (ie, measures of state anxiety, trait anxiety, depression,tains that sensory input represents only one of three majorstate anger, and trait anger). Multiple regression analysis wassources of neural inputs that affect the neuromatrix. The otherperformed to examine the relative contribution of the ve mea-two inputs reect the activity of cognitive-evaluative factors (eg,sures of negative affect in predicting pain. The results of thetonic brain inputs resulting from learning and personality, pha- regression analysis revealed that state anxiety (i.e., transitory orsic inputs resulting from attention and mood) and motivational-situational anxiety) was the only variable that signicantly con-affective factors (eg, the hypothalamic-pituitary-adrenal system,tributed to the prediction of pain. State anxiety accounted forimmune system, and endogenous opiates). The ne