Academic Pain Medicine A Practical Guide to

Rotations Fellowship and Beyond Yury Khelemsky

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Collection Highlights

Questions and Answers in Pain Medicine: A Guide to Board

Exams 1st Edition Michael Suer

From Inquiry to Academic Writing A Practical Guide 4th

Edition Stuart Greene

Evaluating Research in Academic Journals A Practical Guide

to Realistic Evaluation Fred Pyrczak

Doing Academic Research A Practical Guide to Research

Methods and Analysis 1st Edition Ted Gournelos
Becoming a Successful Scholar A Practical Guide to
Academic Achievement in the Medical Professions Guido
Filler

Safety, Health and Environmental Auditing: A Practical

Guide, Second Edition Simon Watson Pain

Genomic Medicine: A Practical Guide Laura J. Tafe

Surgical Pain Management: A Complete Guide to Implantable

and Interventional Pain Therapies 1st Edition Narang

Change Leadership in Higher Education A Practical Guide to

Academic Transformation 1st Edition Jeffrey L. Buller
 Yury Khelemsky
Anuj Malhotra
Karina Gritsenko
Editors

Academic Pain
Medicine
A Practical Guide to Rotations,
Fellowship, and Beyond

123
Academic Pain Medicine
Yury Khelemsky • Anuj Malhotra
Karina Gritsenko
Editors

Academic Pain Medicine

A Practical Guide to Rotations,
Fellowship, and Beyond
Editors
Yury Khelemsky Anuj Malhotra
Pain Medicine Fellowship Pain Medicine Fellowship
Department of Anesthesiology, Perioperative and Department of Anesthesiology, Perioperative and
Pain Medicine Pain Medicine
Department of Neurology Icahn School of Medicine at Mount Sinai
Icahn School of Medicine at Mount Sinai New York, NY
New York, NY USA
USA

Karina Gritsenko
Regional Anesthesia and
Acute Pain Medicine Fellowship
Department of Anesthesiology
Albert Einstein College of Medicine
Montefiore Medical Center
Bronx, NY
USA

ISBN 978-3-030-18004-1    ISBN 978-3-030-18005-8 (eBook)

https://doi.org/10.1007/978-3-030-18005-8

© Springer Nature Switzerland AG 2019

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Preface

The specialty of Pain Medicine is relatively new, when compared to more established fields.
Consequently, the base of required knowledge and skill is in a constant state of expansion and
modification. The core requirements for the Accreditation Council for Graduate Medical
Education (ACGME) accredited pain fellowships did not emerge until about 10 years ago and
have since undergone multiple significant revisions.
There has been a clear, unmet need for a standardized text to be used by fellows in ACGME-­
accredited pain fellowship programs in order to provide a clinically relevant narrative to their
training, as well as help prepare them for certification exams. This work was created to do just
this. Additionally, it may serve as a valuable overview of the field for medical students, resi-
dents, non-physician providers, as well as physicians in other fields.
We believe that this text provides a blueprint for the emerging legitimate specialty of Pain
Medicine and that it provides a common set of ideas for clinicians who have undergone the
rigorous training and certification required in order to have the privilege of alleviating pain and
suffering. And more than anything, we hope that the pages of future iterations of works like
this are filled with new and ever-effective treatments of pain, developed by someone reading
this preface.

New York, NY, USA Yury Khelemsky

Anuj Malhotra
Bronx, NY, USA Karina Gritsenko


v
Contents

1 Anatomy and Physiology: Mechanisms of Nociceptive Transmission�������������������   1

Scott Grubb and George W. Pasvankas
2 Pharmacology of Pain Transmission and Modulation���������������������������������������������   9
Rishi R. Agarwal, Rishi Gaiha, and David R. Walega
3 Development of Pain Systems ����������������������������������������������������������������������������������� 15
Michael Miller, Rahul Sarna, and Awss Zidan
4 Designing, Reporting, and Interpreting Clinical Research Studies
About Treatments for Pain: Evidence-Based Medicine������������������������������������������� 23
Nisheeth Pandey, Joseph Park, and Sukdeb Datta
5 Animal Models of Pain and Ethics of Animal Experimentation����������������������������� 27
Arjun Yerasi and Laxmaiah Manchikanti
6 Taxonomy of Pain Systems����������������������������������������������������������������������������������������� 33
Anuj Malhotra
7 Assessment and Psychology of Pain ������������������������������������������������������������������������� 37
Will Tyson and Anuj Malhotra
8 Placebo and Pain��������������������������������������������������������������������������������������������������������� 43
Thomas Palaia, Christopher Curatolo, and Stelian Serban
9 Epidemiology��������������������������������������������������������������������������������������������������������������� 47
Michael Andreae
10 Psychosocial and Cultural Aspects of Pain��������������������������������������������������������������� 51
Ravi Prasad and Laura Wandner
11 Sex and Gender Issues in Pain����������������������������������������������������������������������������������� 59
Priya Pinto
12 Opioids������������������������������������������������������������������������������������������������������������������������� 63
Kristoffer Padjen, Scott Maddalo, Patrick Milord, Chaim Goldfeiz,
Robert Otterbeck, and Christopher Gharibo
13 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) ������������������������������������������������� 69
Karina Gritsenko
14 Antidepressants and Anticonvulsants����������������������������������������������������������������������� 75
Melinda Aquino
15 Miscellaneous Analgesic Agents��������������������������������������������������������������������������������� 81
Shawn Amin, Christy Anthony, Vincent Reformato, and Andrew G. Kaufman
16 Psychological Treatments������������������������������������������������������������������������������������������� 87
Isaac Cohen

vii
viii Contents

17 Psychiatric Treatment������������������������������������������������������������������������������������������������� 95
Ravi Prasad, Amir Ramezani, Robert McCarron, and Sylvia Malcore
18 Clinical Nerve Function Studies and Imaging��������������������������������������������������������� 105
Soo Y. Kim, John S. Georgy, and Yuriy O. Ivanov
19 Peripheral Nerve Blocks and Lesioning and Surgical Pain Management������������� 111
Alan David Kaye, Elyse M. Cornett, Chris J. Cullom, Susan M. Mothersele,
Yury Rapoport, Burton D. Beakley, Azem Chami, and Vibhav Reddy
20 Surgical Pain Management ��������������������������������������������������������������������������������������� 125
Matthew B. Novitch, Mark R. Jones, Cameran Vakassi, Alexander Haroldson,
and Robert Levy
21 Spinal Cord Stimulation��������������������������������������������������������������������������������������������� 131
Adeepa Singh and Jason Pope
22 Intrathecal Drug Delivery: Indications, Risks, and Complications����������������������� 139
Mark N. Malinowski, Nicholas Bremer, Chong H. Kim, and Timothy R. Deer
23 Physical Medicine and Rehabilitation����������������������������������������������������������������������� 143
Sumeet Arora, Samantha Erosa, and Houman Danesh
24 Stimulation-Produced Analgesia (TENS and Acupuncture)����������������������������������� 153
Max Snyder and Naum Shaparin
25 Work Rehabilitation��������������������������������������������������������������������������������������������������� 159
Andrew Gitkind and Adeepa Singh
26 Complementary and Alternative Medicine��������������������������������������������������������������� 163
Rehan Ali, Jeffrey Ciccone, and Pavan Dalal
27 Acute Pain������������������������������������������������������������������������������������������������������������������� 167
Erica B. John, Marc W. Kaufmann, Richard A. Barnhart, Jaime L. Baratta,
and Eric S. Schwenk
28 Cancer Pain����������������������������������������������������������������������������������������������������������������� 177
Jonathan Silverman and Amitabh Gulati
29 Cervical Radicular Pain��������������������������������������������������������������������������������������������� 211
Carl Noe and Gabor Racz
30 Neck Pain��������������������������������������������������������������������������������������������������������������������� 219
Lowell Shih, Alopi Patel, and Sudhir Diwan
31 Lumbar Radiculopathy ��������������������������������������������������������������������������������������������� 227
Ramsin M. Benyamin, William J. Smith, James Lieber, and Ricardo Vallejo
32 Low Back Pain������������������������������������������������������������������������������������������������������������� 235
Sapan Shah, Julia H. Ding, and Anis Dizdarević
33 Musculoskeletal Pain Joint Pain: Upper Extremities ��������������������������������������������� 243
Melinda Aquino and Yuriy O. Ivanov
34 Musculoskeletal Joint Pain: Lower Extremities������������������������������������������������������� 255
Paul K. Cheng and Magdalena Anitescu
35 Muscle and Myofascial Pain��������������������������������������������������������������������������������������� 277
Rene Przkora, Pavel Balduyeu, and Andrea Trescot
36 Regenerative Medicine����������������������������������������������������������������������������������������������� 283
Jonathan Snitzer, Sunny Patel, Xiao Zheng, Houman Danesh,
and Yury Khelemsky
Contents ix

37 Visceral Pain ��������������������������������������������������������������������������������������������������������������� 291

Leonardo Kapural and Jeremy Naber
38 Chronic Urogenital and Pelvic Pain ������������������������������������������������������������������������� 297
Zakari A. Suleiman and Corey W. Hunter
39 Pain in Pregnancy and Labor ����������������������������������������������������������������������������������� 305
Demetri Koutsospyros and Lawrence Epstein
40 Headache��������������������������������������������������������������������������������������������������������������������� 311
Dmitri Souza, Irena Kiliptch, and Alex Feoktistov
41 Orofacial Pain������������������������������������������������������������������������������������������������������������� 317
Miles Day, Kathryn Glynn, Ryan McKenna, Bhargav Mudda,
and Katrina von-Kriegenbergh
42 Neuropathic Pain��������������������������������������������������������������������������������������������������������� 327
Theodore Eckman and Jianguo Cheng
43 Complex Regional Pain Syndrome��������������������������������������������������������������������������� 333
Nancy S. Lee, Sean Li, and Peter Staats
44 Pain in Infants, Children, and Adolescents�������������������������������������������������������������� 339
Veronica Carullo, Ellise Cappuccio, and Ingrid Fitz-James Antoine
45 Pain in Older Adults (Geriatric)������������������������������������������������������������������������������� 345
David Vahedi and Vinoo Thomas
46 Pain Assessment in Individuals with Limited Ability to Communicate����������������� 351
Victor Tseng and William Caldwell
47 Pain Relief in Persons with Substance Use and Addictive Disorders��������������������� 357
Boleslav Kosharskyy
48 Pain Relief in Areas of Deprivation and Conflict����������������������������������������������������� 365
Sam Nia and Jason H. Epstein
Index������������������������������������������������������������������������������������������������������������������������������������� 371
Contributors

Rishi R. Agarwal, MD Department of Anesthesiology, Northwestern, Chicago, IL, USA

Rehan Ali, MD Icahn School of Medicine, Mount Sinai Department of Anesthesiology,
Division of Pain Medicine, New York, NY, USA
Shawn Amin, DO Anesthesiology – Department of Pain Medicine, Rutgers University – New
Jersey Medical School, Newark, NJ, USA
Michael Andreae, MD Department of Anesthesiology, Penn State Milton S. Hershey Medical
Center, Hershey, PA, USA
Magdalena Anitescu, MD, PhD Department of Anesthesia and Critical Care, University of
Chicago Medicine, Chicago, IL, USA
Christy Anthony, MD Department of Anesthesiology and Pain Management, University
Hospital, Rutgers – NJMS, Newark, NJ, USA
Ingrid Fitz-James Antoine, MD Montefiore Medical Center, Albert Einstein College of
Medicine, Bronx, NY, USA
Melinda Aquino, MD Montefiore Medical Center, Albert Einstein College of Medicine,
Bronx, NY, USA
Sumeet Arora Metro Pain & Vein, Clifton, NJ, USA
Pavel Balduyeu, MD Department of Anesthesiology, College of Medicine, University of
Florida, Gainesville, FL, USA
Jaime L. Baratta, MD Sidney Kimmel Medical College, Thomas Jefferson University,
Philadelphia, PA, USA
Richard A. Barnhart, DO Department of Anesthesiology, Thomas Jefferson University
Hospital, Philadelphia, PA, USA
Burton D. Beakley, MD Department of Anesthesiology, LSU School of Medicine, Shreveport,
LA, USA
Ramsin M. Benyamin, MD, DABIPP Millennium Pain Center, Bloomington, IL, USA
College of Medicine, University of Illinois, Urbana-Champaign, IL, USA
Nicholas Bremer, MD Department of Anesthesiology and Pain Medicine, Columbia
University Medical Center, New York, NY, USA
William Caldwell, DO Department of Anesthesiology, Pain Medicine, Stony Brook
University Hospital, Stony Brook, NY, USA
Ellise Cappuccio, MD Montefiore Medical Center, Albert Einstein College of Medicine,
Bronx, NY, USA

xi
xii Contributors

Veronica Carullo, MD Pediatric Pain Management, Pediatric Anesthesiology Fellowship

Program, Montefiore Medical Center, The University Hospital for Albert Einstein College of
Medicine, New York, NY, USA
Azem Chami, MD Department of Anesthesiology, LSU School of Medicine, Shreveport, LA,
USA
Jianguo Cheng, MD, PhD Departments of Pain Management and Neurosciences, Cleveland
Clinic, Cleveland, OH, USA
Paul K. Cheng, MD Departments of Pain Management and Neurosciences, Cleveland Clinic,
Cleveland, OH, USA
Jeffrey Ciccone, MD Department of Anesthesiology, Perioperative and Pain Medicine, Icahn
School of Medicine at Mount Sinai Health System, New York, NY, USA
Isaac Cohen, MD Frank H. Netter School of Medicine, Quinnipiac University, Hamden, CT,
USA
Elyse M. Cornett, PhD Department of Anesthesiology, LSU School of Medicine, New
Orleans, LA, USA
Chris J. Cullom, MD Department of Anesthesiology, LSU School of Medicine, Shreveport,
LA, USA
Christopher Curatolo, MD, MEM Department of Anesthesiology, Perioperative and Pain
Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Pavan Dalal, MD Department of Anesthesiology, Perioperative and Pain Medicine, Mount
Sinai Hospital, New York, NY, USA
Houman Danesh, MD Department of Anesthesiology, Perioperative and Pain Medicine,
Mount Sinai Hospital, New York, NY, USA
Sukdeb Datta, MD, MBA Department of Anesthesiology, Mount Sinai Medical Center, New
York, NY, USA
Miles Day, MD, DABA-PM, FIPP, DABIPP Department of Anesthesiology and Pain
Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
Timothy R. Deer, MD, DABPM, FIPP The Spine and Nerve Centers of Virginia, Charleston,
WV, USA
Julia H. Ding, MD Department of Anesthesiology, Columbia University Medical Center,
NewYork-Presbyterian Hospital, New York, NY, USA
Sudhir Diwan, MD Manhattan Spine and Pain Medicine, Lenox Hill Hospital, New York,
NY, USA
Anis Dizdarević, MD Department of Anesthesiology and Pain Medicine, Columbia University
Medical Center, New York, NY, USA
Theodore Eckman, MD Allegheny Health Network, Erie, PA, USA
Jason H. Epstein, MD Department of Anesthesiology, James J Peters Veterans Affairs
Medical Center, Bronx, NY, USA
Lawrence Epstein, MD Department of Anesthesiology, Perioperative and Pain Medicine,
Mount Sinai Hospital, New York, NY, USA
Samantha Erosa, MD Department of Physical Medicine and Rehabilitation, Montefiore
Medical Center, Bronx, NY, USA
Contributors xiii

Alex Feoktistov, MD, PhD Clinical Research, Diamond Health Clinic, Glenview, IL, USA
Rishi Gaiha, MD Anesthesiology, Northwestern Hospital, Chicago, IL, USA
John S. Georgy Interventional Pain Medicine, The Spine and Spine and Pain Institute of
New York, New York, NY, USA
Christopher Gharibo, MD Department of Anesthesiology, NYU Langone Medical Center,
New York, NY, USA
Andrew Gitkind, MD Department of Rehabilitation Medicine, Montefiore Medical Center,
Bronx, NY, USA
Kathryn Glynn, MD Department of Anesthesiology and Pain Management, Texas Tech
University Health Sciences Center, Lubbock, TX, USA
Chaim Goldfeiz, MD Department of Anesthesiology, NYU Langone Medical Center, New
York, NY, USA
Karina Gritsenko Department of Anesthesiology, Montefiore Medical Center and Albert
Einstein College of Medicine, Bronx, NY, USA
Scott Grubb, MD Department of Anesthesia and Perioperative Care, University of California
San Francisco, San Francisco, CA, USA
Amitabh Gulati, MD Department of Anesthesiology and Critical Care Medicine, Memorial
Sloan Kettering Cancer Center, New York, NY, USA
Alexander Haroldson Medical College of Wisconsin, Wausau, WI, USA
Corey W. Hunter, MD, FIPP Ainsworth Institute of Pain Management, New York, NY, USA
Yuriy O. Ivanov, DO Physical Medicine and Rehabilitation, Montefiore Medical Center,
Bronx, NY, USA
Erica B. John, MD, BS Department of Anesthesiology and Acute Pain Management, Thomas
Jefferson University, Philadelphia, PA, USA
Mark R. Jones, MD Department of Anesthesiology, Critical Care and Pain Medicine, Beth
Israel Deaconess Medical Center, Boston, MA, USA
Leonardo Kapural, MD, PhD Carolinas Pain Institute & Center for Clinical Research,
Winston-Salem, NC, USA
Andrew G. Kaufman, MD Department of Anesthesiology, Rutgers, New Jersey Medical
School, Newark, NJ, USA
Marc W. Kaufmann, DO Department of Anesthesiology, Thomas Jefferson University
Hospital, Philadelphia, PA, USA
Alan David Kaye, MD, PhD, DABA, DABIPP, DABPM Department of Anesthesiology,
Louisiana State University School of Medicine, Louisiana State University Interim Hospital
and Ochsner Hospital at Kenner, New Orleans, LA, USA
Yury Khelemsky Department of Anesthesiology, Mount Sinai Medical Center, New York,
NY, USA
Chong H. Kim, MD PM&R and Anesthesiology, Case Western Reserve University, Cleveland,
OH, USA
Soo Y. Kim, MD Physical Medicine and Rehabilitation, Montefiore Medical Center, Bronx,
NY, USA
Irena Kiliptch, MD Avalon University School of Medicine, Toronto, ON, Canada
xiv Contributors

Boleslav Kosharskyy, MD Department of Anesthesiology, Montefiore Medical Center and

Albert Einstein College of Medicine, Bronx, NY, USA
Demetri Koutsospyros, MD Department of Anesthesiology, Montefiore Medical Center,
Bronx, NY, USA
Nancy S. Lee, MD Department of Anesthesiology, Montefiore Medical Center, Bronx, NY,
USA
Robert Levy, MD Institute for Neuromodulation, Boca Raton, FL, USA
James Lieber, BS University of Illinois College of Medicine, Urbana, IL, USA
Sean Li, MD Premier Pain Centers, Shrewsbury, NJ, USA
Scott Maddalo NYU Langone Medical Center, New York, NY, USA
Sylvia Malcore Department of Psychiatry and Behavorial Medicine, Spectrum Health, Grand
Rapids, MI, USA
Anuj Malhotra, MD Department of Anesthesiology Perioperative and Pain Medicine, Icahn
School of Medicine at Mount Sinai, New York, NY, USA
Mark N. Malinowski, DO Adena Regional Medical Center, Adena Spine Center, Chillicothe,
OH, USA
Laxmaiah Manchikanti, MD Pain Management Center of Paducah, Paducah, KY, USA
University of Louisville, Louisville, KY, USA
Robert McCarron Department of Psychiatry and Human Behavior, University of California,
Irvine School of Medicine, Orange, CA, USA
Ryan McKenna, MD, MBA Department of Anesthesiology and Pain Management, Texas
Tech University Health Sciences Center, Lubbock, TX, USA
Michael Miller, DO Department of Neurology, SUNY Upstate Medical University, Syracuse,
NY, USA
Patrick Milord, MD, MBA Department of Anesthesiology, NYU Langone Medical Center,
New York, NY, USA
Susan M. Mothersele, MD Department of Anesthesiology, LSU School of Medicine, New
Orleans, LA, USA
Bhargav Mudda, MD Department of Anesthesiology, Texas Tech University Health Sciences
Center, Lubbock, TX, USA
Jeremy Naber, DO Carolinas Pain Institute & Center for Clinical Research, Winston-Salem,
NC, USA
Sam Nia, MD Department of Anesthesiology, UMASS Memorial Healthcare, Worcester,
MA, USA
Carl Noe, MD Department of Anesthesiology and Pain Management, University of Texas
Southwestern Medical Center, Dallas, TX, USA
Matthew B. Novitch, MD Department of Anesthesiology and Critical Care Medicine,
Froedtert Hospital, Milwaukee, WI, USA
Robert Otterbeck, MD Department of Anesthesiology, NYU Langone Medical Center, New
York, NY, USA
Kristoffer Padjen, MD Department of Anesthesiology, NYU Langone Medical Center, New
York, NY, USA
Contributors xv

Thomas Palaia, MD Department of Anesthesiology, Mount Sinai Medical Center, New York,
NY, USA
Nisheeth Pandey, MD Pain Management, Fayette County Memorial Hospital, Washington
Court House, OH, USA
Joseph Park Department of Anesthesiology, Icahn School of Medicine at Mount Sinai, New
York, NY, USA
George W. Pasvankas, MD Department of Anesthesia and Perioperative Care, Pain
Management Center, University of California San Francisco, San Francisco, CA, USA
Alopi Patel, MD Icahn School of Medicine at Mount Sinai, New York, NY, USA
Sunny Patel, MD Icahn School of Medicine at Mount Sinai, New York, NY, USA
Priya Pinto, MD Division of Palliative Medicine and Bioethics, NYU Winthrop Hospital,
Mineola, NY, USA
Jason Pope, MD Evolve Restorative Center, Santa Rosa, CA, USA
Ravi Prasad, PhD Division of Pain Medicine, Stanford University, Redwood City, CA, USA
Rene Przkora, MD, PhD Department of Anesthesiology, College of Medicine, University of
Florida, Gainesville, FL, USA
Gabor Racz, MD Texas Tech University Health Sciences Center, Lubbock, TX, USA
Amir Ramezani Physical Medicine & Rehabilitation, University of California, Davis,
Sacramento, CA, USA
Yury Rapoport, MD Department of Anesthesiology, Tulane School of Medicine, New
Orleans, LA, USA
Vibhav Reddy, MD Department of Anesthesiology, Tulane School of Medicine, New Orleans,
LA, USA
Vincent Reformato, MD Department of Anesthesiology, Rutgers, New Jersey Medical
School, Newark, NJ, USA
Rahul Sarna, MD Pain Specialists of Austin, Austin, TX, USA
Eric S. Schwenk, MD Sidney Kimmel Medical College, Thomas Jefferson University,
Philadelphia, PA, USA
Stelian Serban, MD Department of Anesthesiology Perioperative and Pain Medicine, Icahn
School of Medicine at Mount Sinai, New York, NY, USA
Sapan Shah, MD Department of Anesthesiology, Columbia University Medical Center,
NewYork-Presbyterian Hospital, New York, NY, USA
Naum Shaparin, MD, MBA Department of Anesthesiology, Montefiore Medical Center,
Bronx, NY, USA
Lowell Shih, MD Department of Pain Management, Ochsner health Center, Covington, LA,
USA
Jonathan Silverman, MD Department of Anesthesiology, Weill-Cornell Medical Center,
New York, NY, USA
Adeepa Singh, MD Montefiore Medical Center, New York, NY, USA
William J. Smith, BS Millennium Pain Center, Bloomington, IL, USA
Jonathan Snitzer, MD Pain Management Specialist, Fairview Clinics, Blaine, MN, USA
xvi Contributors

Max Snyder, MD Department of Anesthesiology, Montefiore Medical Center, Bronx, NY,

USA
Dmitri Souza, MD, PhD Western Reserve Hospital, Heritage College of Osteopathic
Medicine, Ohio University, Cuyahoga Falls, OH, USA
Peter Staats, MD Premier Pain Centers, Shrewsbury, NJ, USA
Zakari A. Suleiman, MD, FIPP Department of Anaesthesia, University of Ilorin Teaching
Hospital, Ilorin, Nigeria
Vinoo Thomas, MD Department of Anesthesiology, Mount Sinai Medical Center, New York,
NY, USA
Andrea Trescot, MD Pain and Headache Center, Eagle River, AK, USA
Victor Tseng, MD Division of Regional Anesthesia & Acute Pain Management, Department
of Anesthesiology, Westchester Medical Center, New York Medical College, Valhalla, NY,
USA
Will Tyson, MD Icahn School of Medicine at Mount Sinai, New York, NY, USA
David Vahedi, MD Fellow in Pain Management, Mount Sinai Medical Center, New York,
NY, USA
Cameran Vakassi, MD Department of Anesthesiology, Critical Care and Pain Medicine,
Beth Israel Deaconess Medical Center, Boston, MA, USA
Ricardo Vallejo, MD Illinois Weslayan University, Bloomington, IL, USA
Katrina von-Kriegenbergh, MD Department of Anesthesiology, Pain Medicine, Texas Tech
University Health Sciences Center, Lubbock, TX, USA
David R. Walega, MD, MSCI Division of Pain Medicine, Department of Anesthesiology,
Northwestern University Feinberg School of Medicine, Chicago, IL, USA
Laura Wandner, PhD Walter Reed National Military Medical Center, Bethesda, MD, USA
Arjun Yerasi, MD Department of Anesthesiology, Perioperative and Pain Medicine, Icahn
School of Medicine at Mount Sinai, New York, NY, USA
Xiao Zheng Icahn School of Medicine at Mount Sinai, New York, NY, USA
Awss Zidan, MD Department of Neurology, SUNY Upstate Medical University, Syracuse,
NY, USA
 Anatomy and Physiology: Mechanisms
of Nociceptive Transmission 1
Scott Grubb and George W. Pasvankas

Introduction Cortex

Nociceptive pain is defined as sensation generated from Perception

actual or threatened damage to non-neural tissue and Pain

begins with the encoding of noxious stimuli in the nervous
system [1]. Nociception itself is the initiation of a signal in
peripheral nerves that is of sufficient intensity to trigger
reflex withdrawal, autonomic responses, and/or the per-
Descending pathway
ception of pain by higher-order cortical structures [2]. The
sensation of pain does not necessarily follow directly from Ascending pathway Dorsal root ganglia
nociceptive signaling, however, as pain perception is (Spinothalamic tract)
instead characterized as the unpleasant sensory or emo-
tional experience which results from such signaling.
Figure 1.1 depicts the fundamental process elements of the Modulation Ventral root
nociceptive pain pathway: transduction, transmission, per- Ventral horn
ception, and modulation [3]. Transmission

From peripheral nerves to the integrative network of

the brain, the relay of pain signals is facilitated by a com-
Peripheral nociception
plex system of neural structures, each serving to modulate Transduction

the experience that is the perception of pain. The key pro-

cesses involved in nociception include transduction via Injury
specialized receptive elements and dorsal root ganglia
(DRG), transmission via ascending relay tracts through
the spinal cord and brainstem, and modulation in primary Fig. 1.1 The fundamental components of the nociceptive pain path-
integrative sites in the thalamus and cortex. Each of these way. The system begins at the site of tissue injury which is transduced
into a neuronal signal by peripheral nociceptive fibers. The nociceptive
levels of neuronal signaling contributes to the totality of
signal is then transmitted along the axon of the afferent nerve to syn-
sensory input to the organism, and dysfunction at any apse in the dorsal horn. Second-order projection neurons transmit the
level can contribute to the generation of chronic pain signal to higher order integrative centers in the CNS where pain percep-
states [4]. tion occurs. Finally, pain sensation is modulated by specific integrative
centers in the brain and via descending projection neurons which feed-
back to synapse in the spinal cord [3]

S. Grubb
 eripheral Mechanisms: Primary Peripheral
P
Department of Anesthesia and Perioperative Care, University of Nociceptors, the Dorsal Root Ganglion
California San Francisco, San Francisco, CA, USA (DRG), and Spinal Cord Projections
G. W. Pasvankas (*)
Department of Anesthesia and Perioperative Care, Pain Noxious stimulation is generated through specialized periph-
Management Center, University of California San Francisco, eral structures located throughout tissue in skin, joints, mus-
San Francisco, CA, USA
cle, dura, as well as the adventitia of blood vessels [5]. These
e-mail: [email protected]

© Springer Nature Switzerland AG 2019 1

Y. Khelemsky et al. (eds.), Academic Pain Medicine, https://doi.org/10.1007/978-3-030-18005-8_1
2 S. Grubb and G. W. Pasvankas

nociceptors serve to detect mechanical, chemical, and ther- the spinal cord on the dorsal surface, and synapse in the dor-
mal input which are potentially damaging to tissue and to sal horn. Secondary neurons in the spinal cord project axons
relay those signals to central integrative centers which gener- across the midline to ascend to the thalamus via the lateral
ate protective behaviors [6]. Nociceptors can be polymodal – and ventral spinothalamic tracts (STT). STT cells located in
meaning they may be activated by different forms of noxious the superficial dorsal horn ascend via the lateral STT,
input such as mechanical, chemical, or thermal stimuli – or whereas cells projecting from the deep dorsal horn ascend in
may be specialized to one form of input [6]. A nociceptive the ventral STT (see Fig. 1.3) [5]. Glial cells in the DRG
peripheral nerve is comprised of the peripheral terminal in a serve to support the cell bodies and axonal projections of
target tissue, the axon which conducts an action potential to small and medium-sized nociceptive fibers, even playing a
the CNS, the cell body located in the DRG or cranial nerve role in signal modulation and peripheral sensitization [7].
ganglion, and the central terminal where the cell synapses on Discriminative touch, pressure, and proprioception are trans-
second-order neurons in the CNS [2] (Fig. 1.2). mitted by large, myelinated Aβ fibers, whose cell bodies are
Primary afferent C fibers are small, unmyelinated nerves, also located in the DRG. These somatic mechanosensory
which conduct nociceptive signals at velocities slower than fibers ascend in the dorsal column of the spinal cord to first
2.5 m/s. Aδ fibers are thinly-myelinated nerves and have con- synapse on the dorsal column nuclei of the medulla [5].
duction velocities of 4–30 m/s [5]. C fibers are more numer- Motor neurons exit the spinal cord via the ventral horn and
ous in the dorsal roots than Aδ fibers; however, both C and travel through large, richly myelinated, and rapidly conduct-
Aδ fibers can travel with other somatic and autonomic motor ing fibers contained within the ventral roots; however, auto-
axons. The cell bodies of these nociceptive nerves are invari- nomic motor afferents travel via small, slowly conducting
ably located in the DRG or trigeminal ganglia (CN V), enter fibers [5].

Fig. 1.2 Structure of a Target tissue Peripheral nerve Dorsal root ganglion Dorsal root Spinal cord
primary nociceptor.
Information which reaches
the central terminal is relayed
to second-order neurons in the
CNS, which are invariably
Peripheral terminal Axon Cell body Central terminal
located in the dorsal horn of
the spinal cord [2]

Fig. 1.3 Afferent nociceptor

entry into the spinal cord.
Somatic nociceptors enter the
spinal cord on the dorsal Postsynaptic
surface via the dorsal root. dorsal column
pathway Dorsal
The cell bodies of these
neurons are located within the root
dorsal root ganglia. Primary ganglia
somatic afferents undergo at
least one synapse onto dorsal
horn interneurons, which then
project across the midline to Lateral
ascend in the lateral and PSDC
ventral white matter via the STT
STT. Visceral nociceptive
information, in contrast, is
relayed through the dorsal Ventral
horn and ascends via the Somatic afferents
ipsilateral dorsal column in
Spinothalamic tracts
the postsynaptic dorsal
column pathway [5]
Visceral afferents
1 Anatomy and Physiology: Mechanisms of Nociceptive Transmission 3

Nociceptive peripheral terminals are specialized, high-­ more extensive terminal arborization in the dorsal horn than
threshold endings which express ion channels that respond to somatic nociceptors, which may account for the poor local-
mechanical, chemical, and thermal stimuli. Cool stimuli acti- ization of symptoms and frequent incidence of “referred”
vate the TRPM8 channel, for instance, whereas noxious heat pain in these cases [5].
stimuli activate an array of TRP channels, including
TRPV1-4 and the heat-sensitive potassium channel TREK-1
[8]. By contrast, non-nociceptive sensory neurons express  entral Mechanisms: Spinal and Medullary
C
ion channels which are activated at low-threshold by innocu- Dorsal Horns, Segmental and Brainstem
ous stimuli [2]. Genetic mutations in specific nociceptive
receptor subtypes can produce an array of Hereditary Sensory The first site of nociceptive processing in the CNS is the gray
and Autonomic Neuropathies (HSAN). HSAN Type IV, for matter of the spinal cord dorsal horn. Neurons entering the
example, results from a mutation in the TrkA receptor, dorsal horn arborize to variable degrees and synapse at least
thereby resulting in failure of nerve growth factor (NGF)- once onto local interneurons. Second-order projection neu-
associated receptor differentiation and leading to pain hypo- rons then course to higher-order centers via the contralateral
sensitivity [2]. STT or ipsilateral postsynaptic dorsal column pathway
Glutamate is the primary excitatory neurotransmitter of (PSDC) (see Fig. 1.4). In contrast, discriminative touch and
nociceptive afferents and derangements in glutamate trans- proprioception travel directly via the white matter of the dor-
port or the maintenance of glutamate homeostasis has been sal columns to the dorsal column nuclei of the medulla.
implicated in the development of chronic pain states [9]. An The gray matter of the spinal cord is histologically and
array of small molecules and neuropeptides have been found functionally divided into ten Rexed laminae, with the dorsal
to reinforce and enhance glutamate signaling, including sub- horns comprising laminae I–VI [13]. Visceral nociceptive C
stance P (SP), neurokinin A, galanin, somatostatin, and cal- fibers are seen to project deeply into the dorsal horn, with
citonin gene-related peptide (CGRP). Small, peptidergic wide branching synapses terminating in laminae I, II, V, and
nociceptors are the only source of CGRP in the spinal cord X ipsilaterally. Some visceral fibers even project across the
and, as such, CGRP is frequently used as a molecular marker midline and terminate in laminae V and X contralaterally.
for the study of nociceptive signaling in the spinal cord [10]. This wide degree of arborization explains the relatively poor
Inflammatory cytokines can activate nociceptors at their ter- localization of visceral pain, which is often referred to other
minal endings, the DRG, or the spinal cord and include ade- areas of the body (see Fig. 1.5) [5]. The superficial dorsal
nosine, NO, IL-1, IL-6, and TNFα [5]. In pathologic pain horn (laminae I–III) is where most primary somatic afferent
states, these inflammatory cytokines and signaling molecules C fibers synapse, with laminae II and III comprising the sub-
can lead to further enhanced nociception, increased gluta- stantia gelatinosa [14]. The reserved terminal arborization
mate release, and increased dorsal horn activation, thereby pattern of somatic C fibers in the substantia gelatinosa allows
bolstering the development of central sensitization [11]. for geographic localization of painful stimuli, in contrast to
Fine, discriminative sensory information from skin and the wide branching patterns of visceral C fibers.
joints enters the spinal cord as large, myelinated afferents in Rexed lamina II contains a matrix of interneurons with
the dorsal root. The axons travel along the top of the dorsal large dense-core vesicles of excitatory (e.g., glutamate) and
horn and ascend in the ipsilateral dorsal column white matter inhibitory (e.g., GABA) neurotransmitters [5]. In contrast to
to the medulla. These primary sensory neurons first synapse C fibers, Aδ fibers transmitting mechanical nociceptive
in the dorsal column nuclei of the medulla and then decus- information terminate in lamina I, as well as more deeply in
sate in the medial lemniscus to synapse on the contralateral the spinal cord gray matter of laminae V and X [15].
thalamic nuclei, most notably the ventral posterolateral Distributive interneurons are located within laminae III, IV,
(VPL) nucleus of the thalamus. Primary nociceptive and tem- and VI which project nociceptive information to the hypo-
perature information is carried within afferent myelinated thalamus via the spinohypothalamic tract, and the brainstem
and unmyelinated fibers which enter the dorsal surface of the via the spinoreticular and spinocervical tracts [5]. Areas deep
spinal cord and traverse the top of the dorsal horn via to the dorsal horn extending into laminae VII–X are respon-
Lissauer’s Tract. They then enter the gray matter of the spi- sible for somatic and autonomic motor function. The central
nal cord and widely arborize onto dorsal horn interneurons area of the spinal cord is comprised of laminae X and adja-
[5]. Classically, axons traveling in Lissauer’s Tract have been cent segments of the dorsal horn, and is responsible for the
thought to either ascend or descend only 1–2 spinal segments processing of purely visceral and autonomic nociception [5].
before projecting into the dorsal horn; however, electrophys- Spinal interneurons comprise a majority of the neurons
iologic studies have shown some Aδ-fibers to project as in the dorsal horn and secrete a wide array of modulating
many as five spinal segments rostro-caudally in a rat model neurotransmitters. GABA-ergic interneurons located in
­
[12]. Visceral nociceptive afferents have been found to have lamina II are thought to play an important role in the “gate
4 S. Grubb and G. W. Pasvankas

Fig. 1.4 Ascending

nociceptive pathways in the
spinal cord. Somatic
nociceptors enter the spinal
cord on the dorsal surface,
travel in the Lissauer’s Tract Thalamus
approximately 1–2 spinal
segments along the cranio-­
caudal axis and synapse onto
local interneurons in the gray
matter of the dorsal horn.
Second order projection
neurons then decussate at the
spinal cord level in the Media lemniscus
anterior white commissure
ventral to the central canal
and ascend to the thalamus
via the STT. The lateral STT
has its origins from the
superficial dorsal horn,
whereas the ventral STT
Somatic afferent input to the
projects from the deep dorsal
contralateral spinothalamic tract
horn. Visceral afferent
nociception ascends via the
ipsilateral PSDC pathway [5]
Spinothalamic tract

Visceral afferent input

to the ipsilateral postsynaptic
dorsal column pathway
and spinothalamic tract
bilaterally

Fig. 1.5 Structure of the

dorsal horn. Cutaneous I
nociceptors terminate in the II
substantia gelatinosa of Rexed
III
laminae II and III, whereas
visceral C fibers arborize IV Visceral
V Cutaneous
extensively into laminae II, V,
and X ipsilaterally, and X X
contralaterally [5]
1 Anatomy and Physiology: Mechanisms of Nociceptive Transmission 5

control theory” of nociceptive transmission, whereby nox- The postsynaptic dorsal column pathway (PSDC) is pri-
ious transmissions can be inhibited by somatic mechanical marily responsible for relaying visceral nociceptive input
stimuli [16]. In this model, afferent nociceptive CRGP- [5]. The dorsal column tract is classically considered the
ergic axons synapse onto inhibitory GABA-ergic interneu- main thoroughfare for primary afferent neurons carrying
rons in laminae II, inhibiting them through the secretion of touch, pressure, proprioception, and vibratory sensation;
the glycine and dynorphin. In this way, the signaling of however, animal and human studies support the presence of
downstream projection neurons is enhanced. It is when Aβ a visceral nociceptive tract in the dorsal columns in which
fibers carrying mechanical “touch” information are acti- second-order neurons ascend ipsilaterally to synapse at the
vated that the inhibitory activity of GABA-ergic interneu- gracile and cuneate nuclei [19]. After synapsing in the grac-
rons is promoted and the downstream signal is quieted ile and cuneate nuclei, relay fibers of the PSDC decussate in
[16]. the medulla oblongata via the medial lemniscus and ascend
Nociceptive information arriving via the trigeminal nerve to synapse in the thalamus where the signals are then inte-
from the head, neck, and dura enter the CNS in the caudal grated with other forebrain and cortical structures. The func-
medulla which serves as the functional equivalent to the spi- tional importance of the PSDC pathway is evidenced by the
nal cord dorsal horn [17]. These afferent neurons synapse ability to relieve visceral cancer pain in humans by perform-
onto the spinal trigeminal nucleus which sends second-order ing a limited, midline myelotomy of the dorsal columns [20].
projections via the trigeminal lemniscus to the contralateral Although the PSDC pathway and the STT terminate in
ventral posteromedial (VPM) nucleus of the thalamus [5]. In thalamic relay centers, they both provide abundant supply to
this way, the crossing fibers of the trigeminal lemniscus important parallel medullary, pontine, and midbrain integra-
decussate in the medulla and join the STT to be integrated in tion sites (see Fig. 1.6). Such integrating sites include the
thalamic relays to convey pain and temperature sensation rostral ventral medulla (RVM), the PAG, amygdala, and lim-
from the contralateral face. bic systems [5]. The spinohypothalamic and spinoamygdalar
pathways receive innervation from ascending fibers which
originate primarily in Rexed laminae I and X [21]. These
Central Mechanisms: Thalamocortical – pathways contribute to the emotional and motivational
Ascending Nociceptive Pathways, Higher responses to pain through the generation of anxiety, arousal,
Cortical Processing, and Descending and attention. Autonomic alterations also result from these
Modulation midbrain pathways via changes in sympathetic outflow, heart
rate, and blood pressure. The PAG and the nucleus raphe
The primary relay which transmits nociceptive cutaneous magnus (NRM) are primary sites influencing the descending
and temperature input from the periphery to the CNS is the inhibition of pain transmission [22]. The PAG and the NRM
spinothalamic tract (STT). Discriminative cutaneous and are part of the larger reticular system which balances excit-
temperature nociception project from Rexed laminae I, II, atory and inhibitory nociceptive processing [23]. The spino-
and V and decussate ventral to the central canal via the ante- reticular pathway is in part made up of neurons which project
rior white commissure. These axons then form the contralat- from the spinal cord to the RVM, NRM, and the A7 catechol-
eral white matter of the lateral and anterior STTs and rise to aminergic center of the pons. The spinoreticular tracts con-
synapse in the VPL nucleus of the thalamus [5]. The VPL tribute to descending modulation of pain, cortical and limbic
nucleus of the thalamus serves as the main cortical relay cen- projection, stress responses, and other “anti-nociceptive”
ter for somatosensory input related to pain, temperature, and reflexes such as the escape response [5]. The complex inter-
itch from the contralateral side of the body. The anterior and actions of these brainstem centers with higher-order cortical
lateral STTs, along with ascending fibers which terminate in areas are illustrated by Fig. 1.6, along with contributions
the reticular formation (spinoreticular fibers), periaqueduc- from the STT and PSDC pathway.
tal grey (PAG) (spino-periaqueductal fibers), and hypothala- The RVM is one important area of the brainstem which
mus (spinohypothalamic fibers), are together considered the receives nociceptive input and exerts both descending inhibi-
anterolateral system (ALS) [18]. The ALS stands in contrast tory and excitatory influence on pain transmission. The RVM
to the medial pain pathway that is primarily responsible for is composed of the midline raphe system which contains the
transmitting nociceptive information to limbic structures, serotonergic neurons of the NRM, as well as non-­serotonergic
such as the prefrontal and insular cortices, and the anterior neurons. The NRM has primarily been implicated in the inhi-
cingulate cortex. The limbic system is what generates many bition of nociceptive transmission via projections down the
autonomic and affective responses to pain by integrating dorsolateral funiculus to the spinal cord level [24].
input from a wide array of collateral systems, including the Enkephalinergic connections between the NRM and the dor-
spinoamygdalar, spinoreticular, and spinohypothalamic solateral pons help to potentiate descending control of pain
tracts [5]. transmission. The noradrenergic neurons of the dorsolateral
6 S. Grubb and G. W. Pasvankas

Fig. 1.6 The relationship of

ascending nociceptive tracts Sensory areas
in the brainstem. The primary Cerebral cortex
ascending nociceptive tracts
include the spinothalamic Cingulate cortex
tract and the postsynaptic
dorsal column pathway. Both Midbrain
tracts supply innervation to PAG
brainstem integration sites Medial
DR
which contribute to Thalamus
autonomic, affective, Lateral
neurohormonal, and
modulatory responses to pain. Dorsal column nuclei
A7
The VPL thalamic nucleus is Amygdala Pons
the main cortical relay center Medulla oblongata
Hypothalamus RVM
for the localization of pain, Raphe
whereas the medial thalamus PSDC
projects to the anterior
cingulate cortex which Pain systems
produces affective and
STT
motivational responses to
pain [5]

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 Pharmacology of Pain Transmission
and Modulation 2
Rishi R. Agarwal, Rishi Gaiha, and David R. Walega

Experimental Models: Limitations are owed to vivisection. Examples of animal neuropathic pain
models include: progressive tactile hypersensitivity, which
The human experience of pain is a wholly subjective one, develops months after recovery from sciatic nerve crush in
depending on the perception of the individual experiencing a response to repeated intermittent low-­threshold mechanical
noxious stimulus. Unlike other acute and chronic conditions stimulation of the re-innervated sciatic nerve skin territory [3];
such as myocardial infarction or diabetes for which the spared nerve injury, which is characterized by an early and
degree of severity can be reliably quantified with laboratory sustained increase in stimulus-evoked pain sensitivity in the
values, acute and chronic pain conditions lack similar testing intact skin territory of the spared sural nerve after sectioning
to objectively quantify pain levels. As such, experimental of the two other terminal branches of the sciatic nerve [3]; and
models designed to study pain perception are limited by the hot plate testing that assesses pain behaviors such as paw lick-
inherent lack of consistency between different individuals ing or jumping in response to pain due to heat [4]. An example
experiencing the same noxious stimulus. Nevertheless, the of an animal visceral pain model is the writhing test, in which
evolution of experimental models over the past century has noxious substances (e.g., capsaicin, acetic acid, mustard oil)
enabled a better understanding of pain transmission and are injected intraperitoneally and visceral pain behaviors such
modulation, making possible significant advances in thera- as licking of the abdomen, stretching, and contractions of the
pies and treatments. abdomen are monitored or measured [5]. A less ideal, and
An important and increasingly utilized instrument to arguably inhumane, animal visceral pain model for irritable
characterize mechanisms underlying pathologic pain disor- bowel syndrome involves the use of an inflated balloon tamp
ders is quantitative sensory testing (QST), which allows for applied inside the rectum of rats [6].
static and dynamic forms of testing [1, 2]. Examples of static Clearly, findings from animal models of pain and pain
QSTs include: cold and heat pain threshold, pressure pain behavior do not fully translate into the sensory and emo-
threshold, and 2-point discrimination. Static QSTs are used tional experience of pain in humans. As such, pain models
for threshold determination and provide insight into the basal that are ethically and morally acceptable to perform on con-
state of the nociceptive system. Examples of dynamic QSTs senting humans were developed based on existing animal
include: mechanical wind-up and conditioned pain modula- models. A simple way to organize both animal and human
tion. Dynamic QSTs are used to assess the mechanisms of models of pain is by location of the noxious stimulus applied:
pain processing, such as peripheral and central skin, muscle, or viscera. Commonly used models of pain
sensitization. applied to skin include calibrated filaments (e.g., von Frey
The development of experimental models of pain and filaments), which quantitatively assess the response to touch
knowledge of safety profiles for various analgesic medications by bending when a specific pressure is applied but are not
able to specifically evoke pain as they primarily activate
R. R. Agarwal A-beta fibers, and pressure algometers, which apply stan-
Department of Anesthesiology, Northwestern, Chicago, IL, USA dardized pressure and activate A-delta and C-fibers [7]. A
R. Gaiha (*) classic model of pain applied to muscle is ischemic stimula-
Anesthesiology, Northwestern Hospital, Chicago, IL, USA tion, in which ischemic muscle pain is induced by pneumatic
e-mail: [email protected]
tourniquet inflation [7]. The most ideal model of pain applied
D. R. Walega to the viscera is chemical stimulation, whereby acidic
Division of Pain Medicine, Department of Anesthesiology,
Northwestern University Feinberg School of Medicine, ­chemicals are applied to the esophagus, as this model closely
Chicago, IL, USA resembles clinical inflammation [7].

© Springer Nature Switzerland AG 2019 9

Y. Khelemsky et al. (eds.), Academic Pain Medicine, https://doi.org/10.1007/978-3-030-18005-8_2
10 R. R. Agarwal et al.

Unmyelinated C fibers transmit nociception at less than 2

 eripheral Mechanisms of Pain Transmission
P m/s, and are associated with prolonged burning sensations.
and Modulation Thinly myelinated A-delta fibers transmit nociception at
5–20 m/s and are associated with sharp, intense, tingling
There are three types of primary afferent fibers in the skin sensations.
that are distinguished by conduction velocity (Table 2.1) The processes that lead to the perception of pain involve
[8]. A-beta fibers are large and myelinated, have the fastest the following steps, in order: transduction, transmission,
conduction velocity, and transmit light touch, pressure, modulation, and perception. Tissue injury from mechanical,
and hair movement. Unmyelinated C fibers and thinly thermal, or chemical stimuli results in the release of numer-
myelinated A-delta fibers transmit nociception. ous chemicals including bradykinin, free hydrogen ions,
serotonin, histamine, eicosanoids, nitric oxide, adenosine,
Table 2.1 Chemicals released during peripheral tissue injury
and cytokines (Table 2.2) by various cell types such as dam-
aged tissue cells, macrophages, and mast cells in the skin
Substance Source Effect
(Fig. 2.1) [9]. These, in turn, either directly activate nocicep-
Bradykinin Macrophages and Activates nociceptors
plasma kininogen tors or increase the excitability of (e.g., sensitize) nocicep-
Serotonin Platelets and mast Activates nociceptors tors. These chemical mediators transduce stimuli at the
cells primary afferent fibers of the peripheral nervous system into
Histamine Platelets and mast Produces vasodilation, action potentials that are then transmitted to the spinal cord
cells edema and pruritus
Potentiates the response
via the dorsal root ganglion, which houses the cell bodies of
of nociceptors to the primary afferent fibers.
bradykinin Pain modulation in the periphery involves the recruitment
Prostaglandin Tissue injury and Sensitize nociceptors of inflammatory cells to the site of damage by pro-­
cyclooxygenase inflammatory mediators that not only facilitate the percep-
pathway
Leukotriene Tissue injury and Sensitize nociceptors
tion of pain, but also act to limit pain transmission. For
lipoxygenase pathway example, Substance P released by primary afferent fiber ter-
Hydrogen ions Tissue injury and Hyperalgesia minals in response to tissue damage leads to the activation of
ischemia macrophages and mast cells [10, 11]. Conversely, peripheral
Cytokines Macrophages Excite and sensitize opioid receptors on the same primary afferent fibers receiv-
(interleukins and nociceptors
tumor necrosis ing input from noxious stimuli become upregulated in
factor α) inflammatory environments, allowing endogenous opioids
Adenosine Tissue injury Pain and hyperalgesia (e.g., endorphins), released by inflammatory cells such as
Substance P Substance P activates
Release by peripheral macrophages, monocytes, and lymphocytes, to modulate and
Glutamate nerve terminals macrophages and mast
dampen the pain response to tissue damage. Release of
following injury cells
Glutamate activates endogenous endorphins is thought to be the mechanism by
nociceptors which acupuncture works [12]. The mechanisms behind neu-
Calcitonin Release by peripheral Excitatory effect on rotransmitters and neuropeptides involved in pain modula-
G-related peptide nerve terminals in WDR neurons of the tion are discussed below.
Nerve growth dorsal horn dorsal horn
factor Macrophages Induces heat
hyperalgesia
Sensitizes nociceptors  ynaptic Transmission of Pain in the Dorsal
S
Horn
Table 2.2 Primary afferent fibers
Diameter Conduction
The first synapse in somatosensory processing of informa-
Group (μm) velocity (m/s) Modalities tion from A-delta and C fibers occurs in the spinal dorsal
A (myelinated) horn if the stimulus originates from the body surface
A-alpha 15–20 8–120 Large motor, (Fig. 2.2) or the spinal trigeminal nucleus if it originates
proprioception from the face [13]. These initial synapses in the spinal cord
A-beta 8–15 30–70 Small motor, touch,
occur on the ipsilateral side as the origin of the stimuli. The
pressure
A-gamma 4–8 30–70 Muscle spindle, reflex second-order neurons with which primary afferent fibers
A-delta 3–4 10–30 Pain, temperature synapse are of two predominant types: wide-dynamic-
B (myelinated) 3–4 10–30 Preganglionic range (WDR) neurons and nociceptive-specific (NS) neu-
autonomic rons. WDR cells receive input from A-beta, A-delta, and C
C (unmyelinated) 1–2 1–2 Pain, temperature fibers, and are thus activated by both innocuous and nox-
2 Pharmacology of Pain Transmission and Modulation 11

Peripheral sensory nerve ending

β-Endorphin
H+ Glutamate Opioid drugs
Damanged
tissue
Adenosine AS Inhibitory receptors
IC

Plasma
extravasation A2
iGLuR
Vasodilation
PLT ATP mGLuR
PAF P2X2

µ-opioid Gaba-A SSTR2a M2

Mast cells Serotonin 5HT

PGE2 EP

Histamine H1
PKC
PKA
Macrophages Gene
Bradykinin B2/B1 Regulation

TrkA
NGF
Activation
IL1β IL-1r
TRPV1 Substance P
TNFα H+
IL-6
LIF
Heat

Chemicals released following injury Receptors Inhibitory receptors

TNFα: Tumor necrosis factor alpha B2/B1: Bradykinin receptor B1/ bradykinin receptor B2 SSTR2a: Somatostain
IL-6: Interleukin-6 5HT: 5-hydroxytryptarmine receptors receptor 2
LIF: Leukocyte inhibitory factor IL-1r: Interleukin-1 receptor M2: Muscarinic acetylcholine
IL1β: Interleukin 1 beta H1: Histamine H1 receptor receptor 2
NGF: Nerve growth factor TrkA: Tropomyosin receptor kinase A
PGE2: Prostaglandin E2 EP: Prostaglandin EP2 receptor
PAF: Platelet activating factor P2X2: Purinergic receptor P2X2
PLT: Platelet TRPV1: Transient receptor potential cation channel
ATP: Adenosine triphosphate subfamily V member 1
H+: Hydrogen ion A2: Adenosine A2 receptor
ASIC: Acid-sensing ion channel
IGIuR: lonotropic glutamate receptor
mGIuR: Metabotropic glutamate receptor

Fig. 2.1 Cell types, neurotransmitters, neuropeptides, and receptors involved in peripheral nociception

ious stimuli. NS neurons receive input solely from A-delta  entral Sensitization: Mechanisms
C
and C fibers. and Implications for Treatment of Pain
The ten layers of gray matter of the spinal cord, which
includes the ventral, lateral, and dorsal horns, are organized The “gate control theory” of neuromodulation was devel-
by Rexed’s laminae (I–X) [14]. These laminae can help iden- oped by Melzack and Wall in the 1960s as a way to
tify where the initial synapses between the primary afferent describe the mechanism by which transcutaneous electri-
fibers and second-order neurons occur in the dorsal horn. cal stimulation provides pain relief [15]. The theory sug-
WDR cells are largely concentrated in laminae III through V, gested that input from low-threshold A-beta primary
while NS cell bodies are largely concentrated in laminae I afferent fibers inhibits the response of WDR cells to noci-
and II. The axons of the second-order neurons decussate at 1 ceptive input from A-delta and primary afferent C fibers.
or 2 levels above the level of their cell bodies and ascend to However, present thinking is that the modulation of noci-
the brain via the contralateral anterolateral spinal tracts, ception is likely much more complex than what is
where synapses occur with third-order neurons. Third-order explained by the gate control theory and facilitated by
neurons are located in the brainstem and diencephalon and numerous neurotransmitters released at the spinal level by
transmit nociception to the cerebral cortex. intrinsic spinal neurons (e.g., WDR and NS neurons).
12 R. R. Agarwal et al.

Fig. 2.2 Synapses involved

Primary somatosensory
in somatosensory processing
cortex

Third order neuron:

Run from the thalamus to
primary somatosensory area
for processing

Second order neuron:

Crosses over (decussates)
and travels up the lareal
spinothalmic tract to the
thalamus

First order neuron:

ry Nocieptor at the DRG –
Inju
travels though dorsal root
into the posterior gray horn
of the spinal cord

Indeed, high-frequency spinal cord stimulation accom- Specific ligands and receptors are known to be responsi-
plishes analgesia in patients without causing a paresthesia ble for central sensitization. One well-defined example is the
and thus cannot be explained the gate control theory of interaction between glutamate and the N-methyl-D-aspartic
neuromodulation [16]. Moreover, descending inputs from acid (NMDA) receptor [18]. As detailed earlier, inflamma-
the brainstem to the dorsal root ganglion also modulate tory cells such as macrophages and mast cells influence the
nociception. signals transduced by primary afferent fibers in the periphery
Central sensitization represents a special type of modula- by the release of various chemicals (Table 2.2). These signals
tion at the spinal level in which the capacity for transmission alter the gene transcription patterns in second-order neurons
of nociception is dynamic – exhibiting neuronal plasticity. in the dorsal horn, leading to phosphorylation of the NMDA
This plasticity is caused by an alteration in molecular tran- receptor on the synaptic membranes with an increased neu-
scriptional activity of second-order neurons following a nox- ronal responsiveness to the excitatory neurotransmitter glu-
ious stimulus of sufficient intensity and duration, like tamate. This increased responsiveness allows the
surgical incision, such that the second-order neurons sustain voltage-dependent ion channels to remain open longer due to
a response to nociceptive stimuli beyond the initiating stimu- removal of a magnesium ion from the ion channel when the
lus [17]. A helpful example which illustrates the concept of NMDA receptor is phosphorylated. As a result, second-order
central sensitization is the wind-up phenomenon, whereby neurons in the dorsal horn are activated by subthreshold
repeated stimulation of C fibers at frequencies between 0.5 inputs, and exhibit an increased response to supra-threshold
to 1.0 Hz results in a progressive escalation in the number of inputs.
evoked discharges by primary afferent fibers with a single
stimulus. Furthermore, the now sensitized intrinsic spinal
neurons display an expanded receptive field size, as well as  eurotransmitters Involved in Pain
N
an increase in the number of spontaneous discharges. Thus, Modulation
synaptic input from primary afferent fibers that, prior to sen-
sitization, would be subthreshold now generate an aug- The neurochemistry of the somatosensory processing sys-
mented action potential output in the newly sensitized tem involves three classes of transmitter compounds:
second-order neurons. excitatory neurotransmitters, inhibitory neurotransmitters,
2 Pharmacology of Pain Transmission and Modulation 13

and neuropeptides. These compounds are found in termi- endocannabinoids 2-arachidonoylglycerol (2-AG) and
nals of primary afferent fibers, local circuit neurons, and anandamide may also play a role in pain modulation. While
descending modulatory neurons, and all work to modulate patients and clinicians often anecdotally espouse the bene-
signal transmission of the second-order neurons in the dor- fits of cannabinoids in treating chronic pain, more research
sal horn. is needed into their potential therapeutic benefits.
The amino acids glutamate and aspartate are the most
ubiquitous excitatory neurotransmitters in the nervous sys-
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Thewizard63 It

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