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 to associate editor for the Latin American Journal of Pain, the Argen-patients. Since the late 1990s, there has been a ﬂurry of interest in tinian Journal of Anesthesiology, the Journal of the Spanish Societythe extent to which acute pain can become chronic pain and how of 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 & Women’s 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 ﬁrst anesthesiology-based pain management services in the new pain management techniques, outcome studies with painUnited States. In addition to directing the service, he has served management, 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. Sinatra driven” model for delivering acute pain management with spe-has authored more than 130 scientiﬁc 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 titled emerging technologies in the perioperative arena.Acute Pain: Mechanisms and Management. Dr. Sinatra annually Dr. 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 numerous society committees. Dr. Viscusi has lectured extensively bothDr. Oscar A. de Leon-Casasola is Professor of Anesthesiology and nationally 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.
Acute PainManagement Edited by Raymond S. Sinatra Yale UniversityOscar A. de Leon-Casasola Roswell Park Cancer Institute Brian Ginsberg Duke University Eugene R. Viscusi Thomas Jefferson University Foreword Henry McQuay
ContentsContributors vii SECTION II: CLINICAL ANALGESIAAcknowledgments xiii 11. Qualitative and Quantitative Assessment of Pain 147Foreword: Historical Perspective, Unmet Needs, and Cynthia M. Welchek, Lisa Mastrangelo,Incidence xv Raymond S. Sinatra, and Richard Martinez Henry McQuay 12. The Role of Preventive Multimodal Analgesia and Impact on Patient Outcome 172SECTION I: PAIN PHYSIOLOGY AND PHARMACOLOGY Scott S. Reuben and Asokumar Buvanendran1. Pain Pathways and Acute Pain Processing 3 13. 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 Analgesia 204 M. Khurram Ghori, Yu-Fan (Robert) Zhang, and Pamela E. Macintyre and Raymond S. Sinatra Julia Coldrey3. Patient Variables Inﬂuencing Acute Pain 15. Clinical Applications of Epidural Analgesia 221 Management 33 Daniel B. Maalouf and Spencer S. Liu Joshua Wellington and Yuan-Yi Chia 16. Neuraxial Analgesia with Hydromorphone,4. Acute Pain: A Psychosocial Perspective 41 Morphine, and Fentanyl: Dosing and Safety Francis J. Keefe Guidelines 230 Susan Dabu-Bondoc, Samantha A. Franco, and5. Nonsteroidal Anti-Inﬂammatory Drugs and Raymond S. Sinatra Acetaminophen: Pharmacology for the Future 53 Jon McCormack and Ian Power 17. Regional Anesthesia 245 James Benonis, Jennifer Fortney, David Hardman, and6. Local Anesthetics in Regional Anesthesia and Acute Gavin Martin Pain Management 70 John Butterworth 18. Regional Anesthesia for Acute Pain Management in the Outpatient Setting 2877. Pharmacology of Novel Non-NSAID Analgesics 82 Holly Evans, Karen C. Nielsen, Marcy S. Tucker, and P. M. Lavand’homme and M. F. De Kock Stephen M. Klein8. Pharmacokinetics of Epidural Opioids 102 19. Patient-Controlled Analgesia Devices and Analgesic Bradley Urie and Oscar A. de Leon-Casasola Infusion Pumps 3029. Transitions from Acute to Chronic Pain 109 Benjamin Sherman, Ikay Enu, and Frederick M. Perkins Raymond S. Sinatra10. Molecular Basis and Clinical Implications of Opioid 20. Novel Analgesic Drug Delivery Systems for Acute Tolerance and Opioid-Induced Hyperalgesia 114 Pain Management 323 Larry F. Chu, David Clark, and Martin S. Angst James W. Heitz and Eugene R. Viscusi v
vi Contents21. Nonselective Nonsteroidal Anti-Inﬂammatory 33. Acute Pain Management in Sickle Cell Disease Drugs, COX-2 Inhibitors, and Acetaminophen in Patients 550 Acute Perioperative Pain 332 Jaya L. Varadarajan and Steven J. Weisman Jonathan S. Jahr, Koﬁ N. Donkor, and 34. Acute Pain Management in Patients with Opioid Raymond S. Sinatra Dependence and Substance Abuse 56422. Perioperative Ketamine for Better Postoperative Sukanya Mitra and Raymond S. Sinatra Pain Outcome 366 Manzo Suzuki SECTION IV: SPECIALIST MANAGED PAIN23. Clinical Application of Glucocorticoids, 35. Pain Management Following Colectomy: Antineuropathics, and Other Analgesic Adjuvants A Surgeon’s Perspective 583 for Acute Pain Management 377 Theodore J. Saclarides Johan Raeder and Vegard Dahl 36. Acute Pain Management in the Emergency24. Nonpharmacological Approaches for Acute Pain Department 589 Management 391 Knox H. Todd and James R. Miner Stefan Erceg and Keun Sam Chung 37. The Nurse’s Perspective on Acute Pain25. Opioid-Related Adverse Effects and Treatment Management 597 Options 406 Chris Pasero, Nancy Eksterowicz, and Kok-Yuen Ho and Tong J. Gan Margo McCaffery26. Respiratory Depression: Incidence, Diagnosis, and 38. Role of the Pharmacist in Acute Pain Treatment 416 Management 607 Dermot R. Fitzgibbon Leslie 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 Pain and Implementation Issues 433 Management Specialists 623 Paul Willoughby Amr E. Abouleish and Govindaraj Ranganathan28. Acute Pain Management in the Community 40. Evidence-Based Medicine 630 Hospital Setting 455 Tee Yong Tan and Stephan A. Schug Brian E. Harrington and Joseph Marino 41. Effect of Epidural Analgesia on Postoperative29. Ambulatory Surgical Pain: Economic Aspects and Outcomes 637 Optimal Analgesic Management 476 Marie N. Hanna, Spencer S. Liu, and Tariq M. Malik and Raymond S. Sinatra Christopher L. Wu30. Pediatric Acute Pain Management 487 42. Research in Acute Pain Management 646 Giorgio Ivani, Valeria Mossetti, and Simona Italiano Craig T. Hartrick and Garen Manvelian31. Acute Pain Management for Elderly High-Risk and 43. Quality Improvement Approaches in Acute Pain Cognitively Impaired Patients: Rationale for Management 655 Regional Analgesia 514 Christine Miaskowski Thomas M. Halaszynski, Nousheh Saidi, and 44. The Future of Acute Pain Management 670 Javier Lopez Brian Durkin and Peter S. A. Glass32. Postcesarean Analgesia 537 Kate Miller and Ferne Braveman Index 679
ContributorsChapter 1 Chapter 3Nalini Vadivelu, MD Joshua Wellington, MD, MS CA-3 Resident in Anesthesiology Assistant Professor of Clinical Anesthesia and Physical Department of Anesthesiology Medicine and Rehabilitation Yale University School of Medicine Department of Anesthesia New Haven, CT Indiana University Medical Center Indianapolis, INChristian J. Whitney, MD Associate Professor of Anesthesiology Department of Anesthesiology Yuan-Yi Chia, MD Yale University School of Medicine Associate 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 Medicine Chapter 4 New Haven, CT Francis J. Keefe, PhDChapter 2 Pain 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, CT Jon McCormack, MBChB, FRCA, MRCPYu-Fan (Robert) Zhang, MD Clinical and Surgical Sciences Anaesthesia CA-3 Resident in Anesthesiology Critical Care and Pain Medicine Department of Anesthesiology University of Edinburgh Yale University School of Medicine Royal Inﬁrmary Little France New Haven, CT Edinburgh, UKRaymond S. Sinatra, MD, PhD Ian Power, MD Professor of Anesthesiology Clinical and Surgical Sciences Anaesthesia Director of Acute Pain Management Service Critical Care and Pain Medicine Department of Anesthesiology University of Edinburgh Yale University School of Medicine Royal Inﬁrmary Little France New Haven, CT Edinburgh, UK vii
viii ContributorsChapter 6 Chapter 11John Butterworth, MD Cynthia M. Welchek, RPh, MS Robert K. Stoelting Professor and Chairman Clinical Pharmacist Department of Anesthesia Department of Pharmacy Service Indiana University School of Medicine Yale New Haven Hospital Indianapolis, IN New Haven, CTChapter 7 Lisa Mastrangelo, RN, BC, MS Nurse CoordinatorP. M. Lavand’homme, MD, PhD Acute Pain Management Service Department of Anesthesiology Department of Anesthesiology St Luc Hospital Yale University School of Medicine Universit´ Catholique de Louvain e New Haven, CT Brussels, Belgium Raymond S. Sinatra, MD, PhDM. F. De Kock, MD, PhD Professor of Anesthesiology Department of Anesthesiology Director 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, CT Richard Martinez, MDChapter 8 CA-3 Resident in AnesthesiologyBradley Urie, MD Department of Anesthesiology Fellow, Pain Management Yale University School of Medicine Department of Anesthesiology New Haven, CT University at Buffalo, School of Medicine Buffalo, NY Chapter 12 Scott S. Reuben, MDOscar A. de Leon-Casasola, MD Director of Acute Pain Service Professor and Vice-Chair for Clinical Affairs Department of Anesthesiology Department of Anesthesiology Baystate Medical Center University at Buffalo, School of Medicine Springﬁeld, 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 9 Boston, MAFrederick M. Perkins, MD Asokumar Buvanendran, MD Chief of Anesthesia Associate Professor of Anesthesiology Veterans Administration Medical Center Department of Anesthesiology White River Junction, VT Director 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 Medicine Professor 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 Pain Chapter 14 Management Veterans Affairs Palo Alto Health Care System Pamela E. Macintyre, BMedSc, MBBS, MHA, FANZCA, Palo Alto, CA FFPMANZCA Director of Acute Pain ServiceMartin S. Angst, MD Consultant Anaesthetist Associate Professor Department of Anaesthesia, Pain Medicine and Hyperbaric Department of Anesthesia Medicine Stanford University School of Medicine Royal Adelaide Hospital and University of Adelaide Palo Alto, CA Adelaide, Australia
Contributors ixJulia Coldrey, MBBS(Hons), FANZCA David Hardman, MD Consultant Anaesthetist Assistant Professor of Anesthesiology Department of Anaesthesia, Pain Medicine and Hyperbaric Division of Orthopedic, Plastic and Regional Medicine Anesthesia Royal Adelaide Hospital and University of Adelaide Department of Anesthesiology Adelaide, Australia Duke University Health System Durham, 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 Surgery Anesthesia The Weill Medical College of Cornell University Department of Anesthesiology New York, NY Duke University Health System Durham, NCSpencer S. Liu, MD Clinical Professor of Anesthesiology, Director of Acute Pain Chapter 18 Service Department of Anesthesia Holly Evans, MD, FRCPC Hospital for Special Surgery Assistant Professor The Weill Medical College of Cornell University Department of Anesthesiology New York, NY University of Ottawa Ottawa, Ontario, CanadaChapter 16 Karen C. Nielsen, MDSusan Dabu-Bondoc, MD Assistant Professor Assistant Professor of Anesthesiology Division of Ambulatory Anesthesiology Department of Anesthesiology Department of Anesthesiology Yale University School of Medicine Duke University Medical Center New Haven, CT Durham, 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, CT Department of Anesthesiology Duke University Medical CenterRaymond S. Sinatra, MD, PhD Durham, NC Professor of Anesthesiology Director of Acute Pain Management Service Stephen M. Klein, MD Department of Anesthesiology Associate Professor Yale University School of Medicine Department of Anesthesiology New Haven, CT Duke University Medical Center Durham, NCChapter 17James Benonis, MD Chapter 19 Assistant Professor of Anesthesiology Division of Orthopedic, Plastic and Regional Benjamin Sherman, MD Anesthesia CA-3 Resident in Anesthesiology Department of Anesthesiology Department of Anesthesiology Duke University Health System Acute Pain Management Section Durham, NC Yale University School of Medicine New Haven, CTJennifer Fortney, MD Assistant Professor of Anesthesiology Ikay Enu, MD Division of Orthopedic, Plastic and Regional CA-3 Resident in Anesthesiology Anesthesia Department of Anesthesiology Department of Anesthesiology Acute Pain Management Section Duke University Health System Yale University School of Medicine Durham, NC New Haven, CT
x ContributorsRaymond S. Sinatra, MD, PhD Chapter 24 Professor of Anesthesiology Stefan Erceg, MD Director of Acute Pain Management Service CA-3 Resident in Anesthesiology Department of Anesthesiology Department of Anesthesiology Yale University School of Medicine Pain Management Service New Haven, CT Yale University School of Medicine New Haven, CTChapter 20James W. Heitz, MD Keun Sam Chung, MD Assistant Professor of Anesthesiology and Medicine Associate Professor of Anesthesiology Jefferson Medical College Department of Anesthesiology Thomas Jefferson University Pain Management Service Philadelphia, PA Yale University School of Medicine New Haven, CTEugene R. Viscusi, MD Jefferson Medical College Chapter 25 Thomas Jefferson University Kok-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 UCLA Tong J. Gan, MB, FRCA, FFARCSI Los Angeles, CA Department of Anesthesiology Duke University Medical CenterKoﬁ N. Donkor, PharmD Durham, NC Staff Pharmacist Department of Pharmaceutical Services Chapter 26 UCLA Medical Center Los Angeles, CA Dermot R. Fitzgibbon, MD Associate Professor of AnesthesiologyRaymond S. Sinatra, MD, PhD Adjunct 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, CT Paul Willoughby, MDChapter 22 Associate Professor Department of AnesthesiologyManzo Suzuki, MD Stony Brook Health Sciences Center Instructor Stony Brook, NY Department of Anesthesiology Second Hospital Chapter 28 Nippon Medical School Kanagawa, Japan Brian E. Harrington, MD Staff AnesthesiologistChapter 23 Billings Clinic Billings, MTJohan Raeder, MD, PhD Professor in Anesthesiology Joseph Marino, MD Chairman of Ambulatory Anesthesia Medical Faculty Attending Anesthesiologist University of Oslo Director of Acute Pain Management Service Ullevaal University Hospital Huntington Hospital Oslo, Norway Huntington, NYVegard Dahl, MD, PhD Chapter 29 Head Department of Anaesthesia and Intensive Care Tariq M. Malik, MD Professor in Anesthesiology Assistant Professor of Anesthesiology University of Oslo University of Chicago School of Medicine Asker and Baerum Hospital Department of Anesthesia and Critical Care Rud, Norway Chicago, IL
Contributors xiRaymond S. Sinatra, MD, PhD Chapter 33 Professor of Anesthesiology Jaya L. Varadarajan, MD Director of Acute Pain Management Service Attending Physician Department of Anesthesiology Children’s Hospital of Wisconsin Yale University School of Medicine Assistant Professor of Anesthesiology New Haven, CT Medical College of Wisconsin Milwaukee, WIChapter 30Giorgio Ivani, MD Steven J. Weisman, MD Professor Jane B. Pettit Chair in Pain Management Chairman, Department for the Ladies Staff Children’s Hospital of Wisconsin Doctors Professor of Anesthesiology and Pediatrics Department of Pediatric Anesthesiology and Medical College of Wisconsin Intensive Care Milwaukee, WI Regina Margherita Children’s Hospital Turin, Italy Chapter 34Valeria Mossetti, MD Sukanya Mitra, MD Department of Pediatric Anesthesiology and Reader Intensive Care Department of Anaesthesia and Intensive Care Regina Margherita Children’s Hospital Government Medical College & Hospital Turin, Italy Chandigarh, IndiaSimona Italiano, MD Raymond S. Sinatra, MD, PhD Department of Pediatric Anesthesiology and Professor of Anesthesiology Intensive Care Director of Acute Pain Management Service Regina Margherita Children’s Hospital Department of Anesthesiology Turin, Italy Yale University School of Medicine New 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, CT Department of General Surgery Rush University Medical CenterNousheh Saidi, MD Chicago, IL Assistant Professor of Anesthesiology Department of Anesthesiology Chapter 36 Yale University School of Medicine New Haven, CT Knox H. Todd, MD, MPH Professor of Emergency MedicineJavier Lopez, MD Albert Einstein College of Medicine CA-3 Resident in Anesthesiology Director of the Pain and Emergency Medicine Department of Anesthesiology Institute Yale University School of Medicine Department of Emergency Medicine New Haven, CT Beth Israel Medical Center New 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, CT Minneapolis, MNFerne Braveman, MD Chapter 37 Professor Department of Anesthesiology Chris Pasero, MS, RN-BC, FAAN Yale University School of Medicine Pain Management Educator and Clinical Consultant New Haven, CT El Dorado Hills, CA
xii ContributorsNancy 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, VA Hospital for Special Surgery The Weill Medical College of Cornell UniversityMargo McCaffery, MS, RN-BC, FAAN New York, NY Consultant in the Care of Patients with Pain Los Angeles, CA Christopher L. Wu, MD Associate ProfessorChapter 38 Department of Anesthesiology and Critical CareLeslie N. Schechter, PharmD Medicine Advanced Practice Pharmacist The Johns Hopkins University Thomas Jefferson University Hospital Baltimore, MD Philadelphia, PA Chapter 42Chapter 39 Craig T. Hartrick, MD, DABPM, FIPPAmr E. Abouleish, MD, MBA Anesthesiology Research Professor William Beaumont Hospital Department of Anesthesiology Royal Oak, MI University of Texas Medical Branch Galveston, TX Garen Manvelian, MD Independent Pharmaceutical and Biotechnology IndustryGovindaraj Ranganathan, MD, FRCA Consultant Assistant Professor San Diego, CA Department of Anesthesiology University of Texas Medical Branch Chapter 43 Galveston, TX Christine Miaskowski, RN, PhD, FAAN Professor and Associate Dean for Academic AffairsChapter 40 Department of Physiological NursingTee Yong Tan, MBBS, M Med (Anesthesiology) University of California Department of Anaesthesia San Francisco, CA Alexandra Hospital Singapore, Singapore Chapter 44 Brian Durkin, DOStephan A. Schug, MD, FANZCA, FFPMANZCA Director of Acute Pain Service Department of Anaesthesia and Pain Medicine Assistant Professor of Clinical Anesthesiology Royal Perth Hospital Department of Anesthesiology Perth, 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 University Stony Brook University Medical Center Baltimore, MD Stony Brook, NY
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
Foreword: Historical Perspective, Unmet Needs, and Incidence Henry McQuayIt is a delight and an honor to be asked to write the foreword for this 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 efﬁcacy 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 league and the same procedure was performed by the same surgeon.tables of relative efﬁcacy to say with some authority how well The patient described very severe postoperative pain, qualita-on average the different analgesics compare. This leaves us, of tively and quantitatively quite different from the ﬁrst 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 ﬁrst 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 severe ered 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 ﬂag, but that is not easy to spot giventhe early 1980s, and their policies and education of both patients the 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 difﬁcult approach.cases. Many of the patients whose care causes problems for the The measurement of the analgesic efﬁcacy of preemptiveteams seem, locally for us at least, to be the patients with chronic strategies 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 patient pain initially, then the method is invalid. This is the conundrumadvocacy roles within the institution. Things they may struggle in measurement of the analgesic efﬁcacy 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 ﬂurry 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 how pain 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 out controlled 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 common tic antiepileptic drugs – use PCA in this way and report reducedcause of nerve damage pain and should perhaps be something PCA 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
xvi Foreword Remove Regional Physical Psychologicalthe cause Medication analgesia methods approaches of pain Surgery, Relaxation, splinting High-tech psychoprophylaxis, epidural Low-tech hypnosis infusion, nerve blocks, local local anaesthetic ± anaesthetic ± opioid opioid Non-opioid Opioid aspirin & other Physiotherapy, aspirin & other NSAIDs, NSAIDs, manipulation, TENS, Figure F.2: Relative analgesic efﬁcacy of analgesics in postoperative acupuncture, acetaminophen acetaminophen ice pain: number-needed-to-treat (NNT) for at least 50% pain relief over combinations combinations 6 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 the Henry McQuaysame level as is seen in the “active” group. Unless the pain scores Nufﬁeld Professor of Clinical Anaestheticsare equivalent, it is very difﬁcult to interpret the difference in University of OxfordPCA consumption. We need urgently to establish the validity ofPCA as an outcome measure. REFERENCE The 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;229:55–59.
1 Pain Pathways and Acute Pain Processing Nalini Vadivelu, Christian J. Whitney, and Raymond S. SinatraUnderstanding the anatomical pathways and neurochemical With regard to a more recent classiﬁcation, pain states maymediators involved in noxious transmission and pain percep- be characterized as physiologic, inﬂammatory (nociceptive), ortion is key to optimizing the management of acute and chronic neuropathic. Physiologic pain deﬁnes rapidly perceived nontrau-pain. The International Association for the Study of Pain deﬁnes 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 responses reﬂexes that prevent or minimize tissue injury.can be unpleasant and often debilitating, they serve important Nociceptive pain is deﬁned 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, inhibit disease-related injuries. Nociceptive pain has also been termedmobility thereby enhancing wound healing, and initiate motiva- inﬂammatory 6 because peripheral inﬂammation and inﬂamma-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 as In general, the intensity of nociceptive pain is proportional toanalgesic undermedication, can increase postsurgical/traumatic the magnitude of tissue damage and release of inﬂammatorymorbidity, delay recovery, and lead to development of chronic mediators.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 emphasis crushing, or tearing in character. Visceral nociceptive painis directed to mediators and receptors responsible for noxious deﬁnes 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 N ceral 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 tissue either 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 deﬁned The process of neural sensitization and the clinical termas discomfort persisting 3–6 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 of would not be perceived as painful. These changes, termed hyper-greater clinical importance than deﬁnitions based on duration of pathia10 and allodynia,11 although common following severediscomfort.5 Clinical differentiation between acute and chronic or extensive injuries, are most pronounced in patients devel-pain is outlined in Table 1.1. oping persistent and neuropathic pain. Hyperalgesia can be 3
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 Pain Hyperalgesia Deﬁnes 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 onset 2. Gradual or distinct onset. the area of injury and is associated with ipsilateral (and occasionally3. Short, well characterized 3. Persists after 3–6 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 or diagnosis. Primary hyperalgesia5. Serves a protective function 5. Serves no adaptive purpose Increased pain sensitivity at the injury site6. Effective therapy is available 6. May be refractory to treatment Related to peripheral release of intracellular or humoral noxious mediators Secondary hyperalgesiaclassiﬁed into primary and secondary forms (Table 1.2). Pri-mary hyperalgesia12 reﬂects sensitization of peripheral nocicep- Increased pain sensitivity at adjacent, uninjured sitestors and is characterized by exaggerated responses to thermal Related to changes in excitability of spinal and supraspinal neuronsstimulation at or in regions immediately adjacent to the site Abnormal sensations associated with hyperalgesiaof injury. Secondary hyperalgesia13 involves sensitization withinthe spinal cord and central nervous system (CNS) and includes Hyperpathia (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 primary Paresthesia [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 deﬁned 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 state chronic regional pain syndrome II16 describes pain followingassociated with structural remodeling or “plasticity” changes injury to sensory nerves, whereas discomfort associated withshould be characterized as neuropathic.1 Disease states associ- injury or abnormal activity of sympathetic ﬁbers is termed reﬂexated 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 degeneration and 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 are guide 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 deﬁcits 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 related A 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- ﬁcity theory, was proposed by Descartes.19 The theory suggested that speciﬁc pain ﬁbers carry speciﬁc 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- Normal sation is perceived. More recently, Melzack and Wall21 proposed “Hyperalgesia” the gate control theory and suggested that sensory ﬁbers of dif- Response fering speciﬁcity stimulate second-order spinal neurons (dorsal horn transmission cell or wide dynamic range [WDR] neuron) No Pain Allodynia that, depending on their degree of facilitation or inhibition, ﬁre at varying intensity. Both large- and small-diameter afferents can activate “transmission” cells in dorsal horn; however, large Increasing Stimulus Intensity sensory ﬁbers 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
Pain Pathways and Acute Pain Processing 5Table 1.3: Pathophysiologic Representation of PainCategory Cause Symptom ExamplesPhysiologic Brief exposure to a noxious Rapid yet brief pain perception Touching a pin or hot object stimulusNociceptive/inﬂammatory Somatic or visceral tissue injury Moderate to severe pain, Surgical pain, traumatic pain, with mediators having an described as crushing or stabbing sickle cell crisis impact on intact nervous tissueNeuropathic Damage or dysfunction of Severe lancinating, burning or Neuropathy, CRPS. Postherpetic peripheral nerves or CNS electrical shock like pain NeuralgiaMixed Combined somatic and nervous Combinations of symptoms; soft Low back pain, back surgery pain tissue 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 ﬁrst 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 “ﬂare”3. Intensity: average pain, worst pain, least pain, pain with activity of living TRANSDUCTION4. Topography: focal, dermatomal, diffuse, referred, superﬁcial, deep Transduction27 deﬁnes 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 no chanical stimulation. Noxious stimuli are converted into a cal- difference; incident pain is worse with movement (stretching and cium ion– (Ca2+ ) mediated electrical depolarization within the tearing of injured tissue); intensity changes with touch, pressure, distal ﬁngerlike 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 directly cyclooxygenase 2 enzyme isoform (COX-2) that converts AAsuppressing transmission cells. In contrast, increased activity into biologically active metabolites, including prostaglandin E2in small-diameter ﬁbers 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 ﬁber activity and reducing large key roles as primary activators of peripheral nociceptors. Theyﬁber inhibition.24 Finally, descending inhibition from higher also initiate inﬂammatory 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- Central Descendingsion cells. A schematic representation of the gate control system Control Modulationis 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, inﬂammatory, and neuropathic pain reﬂect sensitization Input T Ascending Action SG 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 interpretation fibersand reaction. The process includes nociceptor activation, neu- Dorsal Horn “Gate”ral 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 supraspinal order transmission cell; SG = substantia gelatinosa cell. (Modiﬁedresponses. The process of central sensitization, particularly from Melzack R and Wall PD, Science. 1965;150(699):971–979.).21
6 Nalini Vadivelu, Christian J. Whitney, and Raymond S. Sinatra Low intensity High intensity Low intensity stimulation Stimulation Stimulation Low threshold mechanoreceptor Sensitized nociceptor Aβ Aδ and C fibers PNS PNS Low threshold High threshold Aβ fiber Aδ and c fiber CNS nociceptors CNS Dorsal Horn Cells Hyperexcitable dorsal horn neuron Innocuous Brief Pain 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) ﬁbers, resulting in physiologic pain perception ofshort duration. Other low-threshold sensory modalities (pressure, vibration, touch) are carried by larger-caliber (low-threshold) ﬁbers. Largeand small ﬁbers make contact with second-order neurons in the dorsal horn. (b) Following tissue injuries and release of noxious mediators,peripheral nociceptors become sensitized and ﬁre repeatedly. Peripheral sensitization occurs in the presence of inﬂammatory 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 ﬁbers 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. (Modiﬁed from Woolf CJ, Salter MW. Neuronalplasticity: increasing the gain in pain. Science. 2000;288(5472):1765–1769.)1 In addition to PGEs, leukotrienes,29 5-hydroxytryptamine Limbic Cortex (5-HT),30 bradykinin (BK),31 and histamine32 released following tissue injury are powerful primary and secondary noxious sensi- Sensory Cortex tizers. 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 Bradykinin’s 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 Ascending the receptor-G-protein complex strengthens inward Na+ ﬂux, Pathway Pathways whereas it weakens outward K+ currents, thereby increasing Central greyNociceptor nociceptor excitability. These locally released substances increase Mid Brain vascular permeability, initiate neurogenic edema, increase noci-Noxious Fiber Dorsal ceptor irritability, and activate adjacent nociceptor endings. The Horn resulting state of peripheral sensitization is termed primary Motor Efferent hyperalgesia. Spinal Cord In 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. Noxious Bradykinin, 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 ﬁbers. Second-order the 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 ﬁbers 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 ﬁbers and 35% of Aδ ﬁbers.37
Pain Pathways and Acute Pain Processing 7 Nociceptive Ending (Primary Afferent Fiber) “Noxious Soup” Ca++ Na+ Peptides- TRP Action Potential sP, CCK, CGRP Local & Vascular Mediators- Traumatic Bradykinin, Mediators- Cytokines K+, H+, Histamine, PGE 5HT ATP TRP Neural Mediators- Ca++ Epinephrine, Norepinephrine Generator Potential R Sinatra 2007 Figure 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 generator potential. Generator potentials depolarize the distal axonal segment and initiate an inward Na+ current and self-propagating action potential. Following tissue injury, cellular mediators (potassium, hydrogen ions, and prostaglandin released from damaged cells, as well as bradykinin [BK] released from damaged vessels) activate the terminal endings (nociceptors) of sensory afferent ﬁbers. Prostaglandin (PGE), syn- thesized by cyclooxygenase 2, is responsible for nociceptor sensitization and plays a key role in peripheral inﬂammation. 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 site of injury. Substance P is responsible for further release of BK and also stimulates release of histamine from mast cells and 5HT from platelets, which further increases vascular permeability (neurogenic edema) and nociceptor irritability. The release of these mediators and others, such as serotonin (5HT) and cytokines, creates a “noxious soup” that exacerbates the inﬂammatory response, recruits adjacent nociceptors, and results in primary hyperalgesia. Reﬂex sympathetic efferent responses may further sensitize nociceptors by releasing noradrenaline and, indirectly, by stimulating further release of BK and sP and leading to peripheral vasoconstriction and trophic changes.Like sP, CGRP38 is produced in the cell bodies of primary of IL-1β result in allodynia and the development of persistentnociceptors located in the dorsal root ganglion. Following axonal pain,42 whereas effective postoperative analgesia decreases proin-transport to peripheral and central terminals, these substances ﬂammatory cytokines levels.43,44 According to Bessler et al,42initiate mechanical and thermal hyperalgesia. When released genetic polymorphisms inﬂuence production of proinﬂamma-at peripheral endings, CGRP enhances PGE39 and histamine- tory cytokines and may contribute to observed interindividualinduced vasodilation and inﬂammatory extravasation. It also differences in postoperative pain intensity scores and variationsprolongs the effect of sP by inhibiting its peripheral metabolic in morphine consumption.breakdown.40 Finally, reﬂex-sympathetic efferent responses also The inﬂammatory mediators and proinﬂammatory 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 identiﬁed 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 of of capsaicin,45 the active chemical compound found in hot pep-distal nociceptor terminals.41 For example, nociceptors are acti- per. The inward ﬂux 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 proinﬂammatory cytokines, such as dorsal horn. The “noxious soup” of local humoral and neu-interleukin- (IL) 1β and IL-6. These cytokines play an impor- ral mediators released following acute tissue injury as well astant role in exacerbating edematous and irritative components the nociceptor response to peripheral injury are summarized inof inﬂammatory pain.42 Studies have shown that elevated levels Figure 1.5.
8 Nalini Vadivelu, Christian J. Whitney, and Raymond S. Sinatra Table 1.5: Classiﬁcation of Primary Afferent Nerve Fibers Characteristic Aβ Aδ C ﬁbers Diameter size Largest Small Very small Degree of myelination Myelinated Thinly myelinated Unmyelinated Conduction velocity Very Fast Fast Slow 30–50 m/s 5–25 m/s <2 m/s Threshold level Low High High Activated by Light touch movement Brief noxious stimulation; Intense and prolonged and vibration also intense and noxious stimuli prolonged noxious stimuli Located in Skin, joints Skin and superﬁcial Skin and superﬁcial tissues; deep somatic and tissues; deep somatic and visceral structures visceral structuresCONDUCTION TRANSMISSIONConduction refers to the propagation of action potentials from Transmission refers to the transfer of noxious impulses from pri-peripheral nociceptive endings via myelinated and unmyelinated mary nociceptors to cells in the spinal cord dorsal horn. Aδ andnerve ﬁbers. Central terminals of these ﬁbers make synaptic con- C ﬁbers are the axons of unipolar neurons that have distal pro-tact with second-order cells in the spinal cord. Nociceptive and jections known as nociceptive endings. Their proximal terminalsnonnoxious nerve ﬁbers are classiﬁed according to their degree enter the dorsal horn of the spinal cord, branch within Lissauer’sof myelination, diameter, and conduction velocity (Table 1.5). tract, and synapse with second-order cells located predominantlyThe largest-diameter sensory ﬁbers, termed Aβ ﬁbers, are gen- in Rexed’s laminae II (substantia gelatinosa) and V (nucleuserally nonnoxious special sensory axons that innervate somatic proprius). The second-order dorsal horn neurons are of twostructures of the skin and joints. Two classes of nociceptive ﬁbers main types. The ﬁrst type, termed nociceptive-speciﬁc neuronsinclude the thin myelinated Aδ and unmyelinated C ﬁbers that (NS), are located in lamina I and respond exclusively to noxiousinnervate skin and a wide variety of other tissues. The Aδ ﬁbers impulses from C ﬁbers. The second type, known as WDR, aretransmit the “ﬁrst pain,” a rapid-onset (<1 s) well-localized, primarily localized in lamina V and respond to both noxious andsharp or stinging sensation of short duration. This perception of innocuous stimuli. Wide dynamic range neurons have variable“ﬁrst pain” alerts the person to actual or potential injury, local- response characteristics such that low-frequency C ﬁber stimula-izes the site of injury, and initiates reﬂex withdrawal responses. tion results in nonpainful sensory transmission, whereas higherThe unmyelinated C ﬁbers, also termed high threshold poly- frequency stimulation leads to gradual increases in WDR neu-modal nociceptive ﬁbers, respond to mechanical, chemical, and ronal discharge and transmission of painful impulses.47 WDRthermal injuries. They are responsible for the perception of neurons can also be suppressed by local inhibitory cells and“second pain,” which has a delayed latency (seconds to min- descending synaptic contacts. The inhibitory actions of SG cells,utes) and is described as a diffuse burning, stabbing sensation as well as the ability of WDR neurons to function as “trans-that is often prolonged and may become progressively more mission cells” that differentially process noxious and innocuousuncomfortable.46 Ion channels found in nociceptive axons as stimuli, provide the physiologic foundation of the gate controlwell as their terminal endings appear to have selective roles in theory. Synaptic connections made within the spinal cord arenoxious conduction. Axonal Na+ ion channels have been classi- presented in Figure 1.6.ﬁed as being either sensitive or resistant (TTX-r) to the puffer ﬁsh Excitatory amino acids such as glutamate (Glu) and aspar-biotoxin tetrodotoxin. The TTX-r isoform is upregulated in sen- tate are responsible for fast synaptic transmission and rapid neu-sitized nerve ﬁbers. Currently available local anesthetics block ronal depolarization. Excitatory amino acids activate ionotropicboth forms; however, development of speciﬁc TTX-r channel amino-3-hydroxyl-5-methyl-4-propionic acid (AMPA) and kai-blockers may provide more selective therapy for neuropathic nite (KAR) receptors that regulate Na+ and K+ ion inﬂux andand chronic inﬂammatory pain. Axonal conduction in nocicep- intraneuronal voltage. AMPA and KAR are relatively imperme-tive ﬁbers culminates in the release of excitatory amino acids able to Ca2+ and other cations.(EAAs) and peptidergic transmitters from presynaptic terminal Each AMPA receptor contains 4 subunits with integral gluta-endings in the dorsal horn. Neuronal-type (N-type) calcium mate binding sites that surround a central cation channel. Ago-channels are concentrated in these terminal endings and open nist binding at two or more sites activates the receptor, openingin response to action potential induced depolarization. Follow- the channel and allowing passage of Na+ ions into the cell.48ing depolarization, these 4-subunit voltage-gated channels allow This brief increase in Na+ ion ﬂux depolarizes second-ordera rapid inﬂux of Ca2+ ions that facilitates release of EAAs. N- spinal neurons, allowing noxious signals to be rapidly trans-type calcium channels may be blocked by conotoxins such as mitted to supraspinal sites of perception. Kainate receptors areziconotide. Speciﬁc ion channels that facilitate or suppress pain also involved in postsynaptic excitation. The KAR cation chan-transmission are presented in Table 1.6. nel regulates both Na+ and K+ ﬂux; however, unlike AMPA,