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Features and Assessments of Pain, Anesthesia, and
Analgesia
This page intentionally left blank
Features and Assessments of
Pain, Anesthesia, and
Analgesia
The Neuroscience of Pain, Anesthetics,
and Analgesics
Edited by
Rajkumar Rajendram
Department of Medicine, King Abdulaziz Medical City, King Abdulaziz International Medical Research
Center, Ministry of National Guard - Health Affairs, Riyadh, Saudi Arabia
College of Medicine, King Saud bin Abdulaziz University of Health Sciences, Riyadh, Saudi Arabia
Vinood B. Patel
Centre for Nutraceuticals, School of Life Sciences, University of Westminster, London, United Kingdom
Victor R. Preedy
King’s College London, London, United Kingdom
Colin R. Martin
Institute for Health and Wellbeing, University of Suffolk, United Kingdom
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Contents
Interventional and surgical analgesic

techniques 11
Contributors xix
Non-drug-based approaches and
Preface xxv noninvasive techniques 11
Palliative and end-of-life situations 11
Conclusion 11
Part I Acknowledgments 11
Setting the scene: General aspects References 11
of anesthesia, analgesics and pain
2. Recent advances in the linkage of
1. The concept of multimorphic attachment and pain: A new review
cancer pain: A new approach from Alessandro Failo
diagnosis to treatment
Introduction 15
Antoine Lemaire Meanings and measurement of attachment 15
Introduction 3 Interlinking attachment and pain 18
Assessing and reassessing cancer pain Attachment and pain: Change in relationship
and patients 4 into different conditions considered 18
Assessing cancer pain 4 Applications to other areas 21
Key facts of cancer pain etiologies 4 Other agents of interest 21
Global assessment of patients 5 Mini-dictionary of terms 22
Other agents of interest: Benefits of Key facts 22
supportive care 6 Summary points 22
Applications to other areas: From References 23
supportive care in cancer to supportive
medicine 6 3. The management of pain in older
The concept of multimorphic cancer people
pain 6 Felicity Veal and Kelsey Ng
Key facts of criteria defining the
multimorphic nature of cancer pain 7 Introduction 27
Treatment strategies in multimorphic Pain perception in the elderly 28
cancer pain 7 Assessing pain in older people 28
Key facts of WHO cancer pain management Pharmacokinetic and pharmacodynamic
guiding principles 8 changes affecting older people 29
Drug-based management of nociceptive Overview of management of pain
cancer-related pain 8 in older people 30
Summary points: Strong opioids in cancer Paracetamol 31
pain management 10 Opioids 32
Drug-based treatments for cancer-related Adjuvant analgesics 32
neuropathic pain 10 Summary of the pharmacological
Management of bone pain 10 management of pain in older people 33
v
vi Contents
Application to other areas 33 Mini-dictionary of terms 54

Other agents of interest 33 Key facts 54
Mini-dictionary of terms 33 Summary 54
Summary points 33 References 55
References 34
6. Analgesia-first sedation and
4. Anesthesia and body mass: nonopioid multimodal analgesia in
Epidural depth and beyond the intensive care unit
Mehmet Canturk John W. Devlin and Paul M. Szumita
Introduction 37 Introduction 57
Preoperative assessment 37 Pain and its assessment in critically ill adults 58
Assessment of respiratory system 37 Assessment-driven protocols 58
Assessment of cardiovascular system 38 Opioid choice, route of administration, and
Assessment of endocrine and dosing 59
musculoskeletal systems 38 Analgosedation 62
Intraoperative management 39 Multimodal nonopioid analgesia use 63
Induction of anesthesia, anesthetic agents, Applications to other areas 65
and muscle relaxants 39 Mini-dictionary of terms 65
Thiopental sodium 39 Summary points 66
Propofol 40 References 66
Opioids 40
Neuromuscular-blocking agents and 7. The multidisciplinary Acute Pain
antagonists 40 Service: Features and experiences
Volatile anesthetics 40
Regional anesthesia 40 Turi Stefano, Deni Francesco,
Marmiere Marilena, Meani Renato, and
Cessation of anesthesia and postoperative
Beretta Luigi
care 42
Applications to other areas 42 Introduction 69
Mini-dictionary of terms 42 The history of Acute Pain Services 70
Key facts of anesthesia and body mass: Basic characteristics of an Acute Pain Service 71
Epidural depth and beyond 42 Acute Pain Service and clinical outcome 72
Summary points 42 The diffusion of Acute Pain Services 74
References 43 The main clinical experiences regarding the
establishment of an Acute Pain Service 74
5. Anesthetics and analgesic activities Conclusion 76
of herbal medicine: Review of the Application to other areas 76
possible mechanism of action Other agents of interest 76
Key facts—Mini-dictionary 76
U.G. Chandrika and Ureshani Karunarathna Summary points 77
Introduction 47 References 77
Local anesthetics herbs 47
Mechanisms of local anesthetics 47 8. Monitoring anesthesia:
General anesthetics herbs 50 Electroencephalography and
Passiflora incarnata 50 beyond
Valerian officinalis 51
Mengmeng Chen and Wangning ShangGuan
Genus Panax 51
Hypericum perforatum 52 Introduction 79
Potential hazards of anesthetics herbal Raw electroencephalography 80
medicine 53 Influence on raw EEG 81
Application of anesthetics herbal medicine 53 Bispectral index 82
Conclusion 53 Limitations and influence on BIS 82
Applications to other areas 53 Evoked potential 83
Contents vii
Somatosensory evoked potential and visual Prophylactic migraine treatment 108

evoked potential 83 β-Blockers 109
Auditory evoked potential 83 Antiepileptics (also known as
Entropy 84 neuromodulators) 109
Narcotrend 84 Antidepressants 109
Cerebral state index 86 Calcium channel blockers 110
Applications to other areas 86 Angiotensin converting enzyme
Mini-dictionary of terms 87 inhibitors, and angiotensin II
Key facts 87 receptor blockers 110
Key facts of raw EEG 87 OnabotulinumtoxinA (Botox) 110
Summary points 87 CGRP monoclonal antibodies 110
References 87 Nonpharmacological approach 110
Exercise based on cognitive behavioral
therapy 110
Part II Conclusion 113
Applications to other areas 113
The syndromes of pain Mini-dictionary of terms 113
Key facts 113
9. Cluster headache and pain: Summary points 114
Features and treatments References 114
R.B. Brandt, J. Haan, G.M. Terwindt, and
R. Fronczek
11. Complex regional pain syndrome
Introduction 93
Epidemiology 93 C. Ryan Phillips, Derek M. Miletich, and
Lynita Mullins
Rhythmicity 94
Pathophysiology 95 Introduction 117
Trigeminal nerve 95 Diagnosis 117
Autonomic system 95 Pathophysiology 118
Hypothalamus 95 Management 118
Genetics 95 Pharmacologic treatment 119
Trigeminal autonomic cephalalgias 96 Anticonvulsants 119
Treatment 98 Antidepressants 119
Pharmacological treatments 98 Antihypertensives and α-adrenergic
Neuromodulatory treatments 100 antagonists 119
Applications to other areas 100 Antiinflammatory drugs 120
Other agents of interest 101 Bisphosphonates 120
Conclusion 101 Calcitonin 121
Mini-dictionary of terms 101 Cannabis 121
Key facts/summary points 101 IVIG 121
References 102 Naltrexone 121
NMDA receptor antagonists 121
10. Migraine and pain: Features and Opioids 121
treatments Interventional treatment 121
Sympathetic nerve blocks 121
Javier Dı́az de Terán and Alfonso Gil-Martı́nez Intravenous regional anesthesia 122
Features 105 Spinal cord stimulation 122
Chronic migraine 106 Applications to other areas 122
Treatments 106 Other agents of interest 122
Acute migraine treatment 106 Mini-dictionary of terms 123
Nonspecific acute treatment 107 Key facts 123
Specific acute treatment 107 Summary points 123
Future 108 References 124
viii Contents
12. Phantom limb pain Early life stress in humans including

maternal deprivation 156
Derek M. Miletich, Lynita Mullins, and Environmental enrichment as a potential
C. Ryan Phillips
intervention against the effects of MD 156
Introduction 127 Applications to other areas 158
Diagnosis 127 Other agents of interest 158
Pathophysiology 128 Mini-dictionary of terms 159
Peripheral 128 Key facts 159
Spinal 130 Key facts of maternal deprivation 159
Supraspinal (brain) 130 Key facts of early-life stress 159
Management 132 Summary points 159
Prevention 132 References 159
Treatment 133
Mini-dictionary of terms 136 15. Giving birth and pain
Key facts 136
Summary points 136 Pelin Corman Dincer
Disclaimer 136 Introduction 163
References 136 Modes of delivery 163
Stages of delivery 164
13. Painful diabetic neuropathy: The Pain treatment in giving birth 165
roles of microglia Pharmacologic treatment 165
Neuraxial analgesia and anesthesia 167
Che Aishah Nazariah Ismail and Idris Long
Postpartum pain 168
Introduction 139 Nonpharmacological treatment 169
Painful diabetic neuropathy 140 Application to other areas 170
Microglia 141 Mini-dictionary of terms 170
Microglial activation during neuropathic Key facts 170
pain 143 Key facts of giving birth and pain 170
Central glia-neuronal interaction 143 Summary points 170
Conclusion 144 References 171
Other agents of interest 145 16. Abdominal pain in gastroparesis
Mini-dictionary of terms 146
Olubunmi Oladunjoye, Asad Jehangir,
Key facts 146 Adeolu Oladunjoye, Anam Qureshi,
Key facts of Pregabalin 146 Zubair Malik, and Henry P. Parkman
Key facts of duloxetine 146
Summary points 146 Introduction 173
References 147 Types of gastroparesis 174
Symptoms of gastroparesis 174
14. Maternal deprivation and Abdominal pain in gastroparesis 174
Symptom assessment in gastroparesis 176
nociception
Physical examination of gastroparesis
Liciane Fernandes Medeiros, patients 177
Dirson João Stein, Bettega Costa Lopes, and Diagnosis of gastroparesis 177
Iraci L.S. Torres Treatment of gastroparesis 177
Introduction 149 Dietary modifications 177
Development of nociceptive pathways 150 Pharmacologic treatments 178
Maternal deprivation 151 Endoscopic and surgical treatments 179
Maternal deprivation and nociception: Treatment of abdominal pain in
Preclinical perspectives 151 gastroparesis 180
Maternal deprivation and nociception: Neuromodulators 180
Signaling pathways changes 154 Antispasmodics 182
Contents ix
Cannabinoids 182 Summary points 208

Nonsteroidal antiinflammatory drugs 183 References 208
Opiate analgesics 183
Celiac plexus block 184 19. Linking the heart and pain:
Treatment of chronic abdominal wall pain 184 Physiological and
Conclusion 184 psychophysiological mechanisms
Key facts 184 Dmitry M. Davydov
Summary points 185 Introduction 211
References 185 The history of the subject 212
Aspects related to (i, ii) a hypertension-
17. Appendicitis and related related hypoalgesia phenomenon in
abdominal pain chronic and acute pain conditions and (iii)
a pain-killing etiology of the essential
Marcos Prada-Arias
(primary) hypertension 212
Introduction 189 Aspects related to (iv) the effectiveness of
Etiology 189 pain management prediction and
Pathophysiology 190 monitoring by cardiovascular measures
Natural history models 190 and to (v) effective pain control by
Typical presentation 192 cardiovascular mechanisms with
Atypical presentation 192 pain-killing effects 213
Inflammatory markers 192 An aspect related to (vi) the pain-o-meter
Clinical prediction rules and imaging tests 193 technology 214
Management 193 An aspect related to (vii) the baroreflex
Surgical approach and complications 194 control of blood volume and pressure
Applications to other areas 194 fluctuations in response to posture or
Other agents of interest 194 body position changes in patients with
Mini-dictionary of terms 197 pain 214
Key facts 197 Summarizing the current knowledge of
Summary points 197 heart and pain relationships 215
References 198 Applications to other areas 217
Other areas of interest 219
18. Ovarian hormones, site-specific Mini-dictionary of terms 219
nociception, and hypertension Key facts of the issue associated with heart
and pain interactions and related
Bruna Maitan Santos, challenges 220
Glauce Crivelaro Nascimento, and
Luiz Guilherme S. Branco Summary points 220
References 221
Introduction 201
Nociception mechanisms and modulation 20. Chronic pain in military veterans
in hypertension: An overview 202
Nociception and blood pressure 203 Ariel Baria, Nancy Liu, Quinn Wonders, and
Orofacial nociception 204 Sanjog Pangarkar
Sex differences and ovarian hormones 204 Introduction 225
Normotensive patients and rodent models 204 Theoretical models of chronic pain 226
Hypertensive patients and spontaneously Military basic training and rates of
hypertensive rats (SHR) rodent model 205 injury 226
Applications to other areas 207 Combat-related injuries in military
Other agents of interest 207 personnel 227
Mini-dictionary of terms 207 Types of chronic pain in veterans 227
Key facts 208 Comorbid conditions in veterans with
Key facts of sex differences in pain 208 chronic pain 227
x Contents
Psychological comorbidities and social Possible pharmacological targets for breast

factors in veterans with chronic pain 228 cancer pain relief 251
Depression, anxiety, PTSD, substance use Cancer pain treatment by
disorder 228 nonpharmacological treatments 252
Socioeconomic challenges 228 Conclusions 252
Pain assessment and treatment 229 Applications to other areas 252
Nonpharmacologic pain modalities 229 Other agents of interest 252
Conclusion 231 Mini-dictionary of terms 253
Applications to other areas 231 Key facts 253
Other agents of interest 231 Key facts of breast cancer-induced pain 253
Mini-dictionary of terms 231 Key facts of chronic pain management 253
Key facts of chronic pain in military veterans 232 Summary points 253
References 232
23. Postoperative pain after
21. Nociception during surgery rhinoplasty and rhinologic surgery
Munetaka Hirose Andre Shomorony, Arron M. Cole,
Matthew Kim, and Anthony P. Sclafani
Introduction 235
Nociceptive pathway during surgery 236 Introduction 257
Monitoring of nociception under general Rhinoplasty 257
anesthesia 237 Septoplasty 257
Intraoperative nociception and Rhinologic surgery 258
postoperative complications 239 Intraoperative analgesia and anesthesia 258
Effects of intraoperative nociception on Rhinoplasty 258
postoperative pain 240 Septoplasty 259
Applications to other areas 240 Rhinologic surgery 259
Monitoring of nociception in the awake state 240 Postoperative pain management 259
Somatosensory processing and monitoring Sources of postoperative pain 259
of nociception: A hypothesis 241 Assessment of pain after surgery 260
Other agents of interest 242 Modalities of management of
Mini-dictionary of terms 242 postoperative pain 260
Key facts 242 Conclusion 262
Key facts of the Somato-sympathetic reflex 242 Applications to other areas 262
Summary points 242 Other agents of interest 262
References 242 Mini-dictionary of terms 262
Key facts 262
22. Breast cancer and nociceptione Summary points 263
References 263
Amanda Spring de Almeida and
Gabriela Trevisan
24. Pain response, neonates, and
Introduction 247 venipuncture
Treatments for breast cancer-induced pain 247
Limitations of cancer pain treatments 248 Hardeep Kaur and Gaurav Mahajan
Bone pain in breast cancer 249 Introduction 265
Treatments of bone pain in breast cancer 249 Pathophysiology of pain and CNS effects 265
Side effects observed for the treatments of Pain assessment tools 266
bone cancer pain 249 Problems in assessing neonatal pain 268
Animal models of breast cancer pain: Breast Pain relief measures 268
inoculation models 250 Conclusion 271
Animal models of breast cancer pain: A brief Application to other areas 272
history of bone inoculation models 251 Other agents of interest 272
Animal models of breast cancer pain: Mini-dictionary of terms 272
Distinct bone inoculation models 251 Key facts 272
Contents xi
Summary points 272 Low-back pain mechanisms in computer

Conflict of interest 273 and smartphone users 292
References 273 Individual risks factors 293
Further reading 273 Physical risks factors for the development of
pain 293
25. Carpal tunnel syndrome and Psychosocial risks factors 294
pain Physical activity to prevent and manage
musculoskeletal pain in computer and
Rodrigo Núñez-Cort
es, smartphone users 295
Carlos Cruz-Montecinos, Claudio Tapia,
Paula Pino Pommer, and Sofı́a P
erez-Alenda Ergonomics to prevent occupational
musculoskeletal pain in computer and
Introduction 275 smartphone users 297
Median nerve compression 275 Applications to other areas 297
Applications to other areas 276 Other agents of interest 297
Considerations for evaluation 276 Mini-dictionary of terms 298
Conservative treatment 278 Key facts 298
Other agents of interest 278 Key facts of risk factors 298
Surgical treatment 278 Key facts of interventions in computer users 298
Psychosocial aspects 280 Summary points 298
Mini-dictionary of terms 280 References 298
Key facts 281
Summary points 281
Acknowledgments 281
Part III
References 281
Interlinking anesthesia, analgesics
26. Pain and HIV and pain
Sara Pullen 28. Health professionals’ and lay
Introduction 285 people’s positions regarding the
Etiology of chronic pain in HIV 285 use of analgesics in cancer cases
HIV-associated distal symmetric
Etienne Mullet and Paul Clay Sorum
polyneuropathy 286
Current pain management 286 Introduction 305
HIV, pain, and opioid use 286 Studies of clinicians and the public 305
Nonpharmacologic approaches to Mapping general practitioner’s positions
HIV-related pain 287 regarding the use of opioids 306
Future steps 288 Mapping lay people’s and health
Applications to other areas 288 professionals’ positions on the use of
Mini-dictionary of terms 289 analgesics in postoperative pain
Key facts 289 management 307
Key facts of HIV and pain 289 Mapping lay people’s and health
Summary points 289 professionals’ positions regarding the use
References 289 of morphine to relieve intense pain 309
Mapping lay people’s and health
27. Pain mechanisms in computer and professionals’ positions regarding
smartphone users temporary or terminal sedation 310
General discussion 312
Alberto Marcos Heredia-Rizo, Applications to other areas 313
Pascal Madeleine, and Grace P.Y. Szeto
Introduction 291 Key facts 313
Origins and mechanisms of neck-shoulder Summary points 314
pain 291 References 314
xii Contents
29. Manual compression at myofascial Systemic nonopioid analgesics 334

trigger points ameliorates Paracetamol 334
musculoskeletal pain Nonsteroidal antiinflammatory drugs
(NSAIDs) 334
Kouichi Takamoto, Susumu Urakawa, Other agents of interest 335
Shigekazu Sakai, Taketoshi Ono, and Ketamine 335
Hisao Nishijo
Systemic magnesium 335
Introduction 317 Systemic lidocaine 335
Link between MTrPs and musculoskeletal α2-Agonists 335
pain 318 Glucocorticoids 336
Low-back pain 318 Systemic opioid analgesics 336
Neck pain 318 Regional anesthesia, local anesthesia, and
Shoulder pain 318 site infiltration with local anesthetics 336
Knee pain 320 Neuraxial analgesia (epidural and
Other body regions 320 spinal) 336
Diagnosis of MTrPs 320 Transversus abdominis plane blocks 337
Effects of compression at MTrPs for Paravertebral blocks 337
musculoskeletal pain 320 Local infiltration 337
Low-back pain 320 Populations that need special consideration
Neck pain 322 in treating PSP 337
Shoulder pain 323 Children 337
Knee pain 323 Obese patients and patients with chronic
Pain in other body regions 323 obstructive pulmonary disease (COPD) 337
Possible mechanisms of MTrP compression Patients receiving long-term opioids 338
effects 323 Application of MA to other areas 338
Applications to other areas 325 Conclusions 338
Mini-dictionary of terms 326 Application to other areas 338
Key facts of MTrP compression for Other agents of interest 338
musculoskeletal pain 326 Key facts 338
Summary points 326 Mini-dictionary of terms 339
References 326 Summary points 339
References 339
30. Multimodal analgesia and
postsurgical pain 31. Pain, ultrasound-guided Pecs II
Martina Rekatsina, Antonella Paladini,
block, and general anesthesia
Giorgia Saltelli, and Giustino Varrassi A.A. Gde Putra Semara Jaya,
Marilaeta Cindryani, and
Introduction 329 Tjokorda Gde Agung Senapathi
Definition and classification of PSP 329
Incidence of PSP and CPSP 329 Introduction 343
Pathophysiology of postoperative pain 330 Acute and chronic postoperative pain in
Peripheral sensitization, central breast surgery 343
sensitization, and neuroplastic changes in General anesthesia: A brief description 344
the brain after incision 331 Technical description of ultrasound-guided
Importance of PSP control 331 Pecs II block 345
Risk factors for CPSP 332 Clinical application ultrasound-guided Pecs
Evaluation of pain intensity 332 II block 347
PSP management: Enhanced recovery after Pectoral nerves, intercostal nerve, and long
surgery programs (ERAS)-preemptive, thoracic nerve 348
preventive, and multimodal analgesia Applications to other areas 348
(MA) 333 Other agents of interest 348
Framework of multimodal analgesia (MA) 333 Mini-dictionary of terms 349
Nonpharmacological interventions 334 Key facts of ultrasound-guided Pecs II block 350
Contents xiii
Summary points 351 Damage control resuscitation 376

References 351 Conclusion 377
32. Pain control during prostate biopsy Other agents of interest 377
and evolution of local anesthesia Mini-dictionary of terms 377
techniques Key facts 377
Key facts of ketamine 377
€
Mustafa Suat Bolat, Onder Cinar, Ali Batur Key facts of point of injury care 378
(Furkan), Ramazan Aşcı, and
Summary points 378
Recep B€uy€ukalpelli
References 378
Introduction 353
Why is prostate cancer significant? 353 35. Spinal anesthesia: Applications to
Neuroanatomy of the prostate 354 cesarean section and pain
History of prostate biopsy 355
Different numbers and sites of infiltration 357 Reyhan Arslantas
Applications of local anesthetics to other Introduction 381
areas 359 History of spinal anesthesia in the field of
Mini dictionary 359 obstetrics 381
Key facts 360 Spinal technique 381
Summary points 360 Anatomy 382
References 360 Preparation 382
Choice of spinal medication 383
33. Pain reduction in cosmetic Bupivacaine 383
injections: Fillers and beyond Ropivacaine 384
Levobupivacaine 384
Hamid Reza Fallahi, Roya Sabzian,
Seied Omid Keyhan, and Dana Zandian Chloroprocaine 384
Lidocaine 384
Introduction 363 Intrathecal opioids 384
Needle fear 363 Lipophilic opioids 384
Psychological intervention 364 Hydrophilic opioids 384
Vibration 364 Other adjuvants 385
Vibration safety 366 Continuous spinal anesthesia 385
Disadvantages 366 Intraoperative management 385
Local anesthesia 366 Recovery from spinal anesthesia 386
Disadvantages 367 Postoperative complications 386
Injecting anesthetics techniques 368 Conclusion 387
Vapocoolant anesthesia 368 Application to other areas 387
Applications to other areas 369 Other agents of interest 387
Other agents of interest 370 Mini-dictionary of terms 387
Mini-dictionary of terms 370 Key facts 387
Key facts 370 Summary points 387
References 370
36. Postoperative pain management:
34. Anesthesia and combat-related Truncal blocks in thoracic surgery
extremity injury
Gulbin Tore Altun
Robert (Trey) H. Burch, III
Introduction 391
Introduction 373 Pain management for thoracic surgery
Anesthesia and war 374 patients within ERAS (enhanced recovery
Acute pain 374 after surgery) protocols 392
Regional anesthesia in extremity injury 375 Multimodal analgesia 392
Osseointegration and targeted muscle Truncal blocks 392
reinnervation 376 Pectoral block type I and II 392
xiv Contents
Introduction 392 Indications 409

Indications 392 Technique 409
Technique 393 Complications 409
Complications 394 Ilioinguinal nerve and iliohypogastric nerve
Serratus anterior plane block (SAPB) 394 blocks 409
Indications 394 Indications 409
Technique 394 Technique 410
Complications 395 Complications 410
Paravertebral block (PVB) 395 Paravertebral block 410
Intercostal block 396 Intercostal block 411
Retrolaminar block (RLB) 398 Quadratus lumborum block 412
Erector spinae plane block (ESPB) 399 Erector spinae plane block 414
Truncal blocks contraindications 400 Transversalis fascia plane block 415
Truncal blocks postprocedure checks 400 Introduction 415
Equipment 400 Indications 415
Conclusion 401 Technique 415
Application to other areas 401 Complications 415
Other agents of interest 401 Contraindications in truncal blocks 415
Mini-dictionary of terms 401 Preparation for truncal blocks 416
Key facts 402 Equipment 416
Summary points 402 Postprocedure 416
References 402 Conclusion 416
Application to other areas 416
37. Postoperative pain management: Other agents of interest 416
Truncal blocks in general surgery Mini-dictionary of terms 416
Key facts 417
Gulbin Tore Altun Summary points 417
Introduction 405 References 417
Truncal blocks 406
Transversus abdominis plane block 406 38. Linking analgesia, epidural
Introduction 406 oxycodone, pain, and laparoscopy
Indications 406
Merja Kokki and Hannu Kokki
Technique 407
Complications 408 Introduction 421
Rectus sheath block 408 Laparoscopy 422
Introduction 408 Pain after laparoscopy 422
Contents xv
Pain treatment after laparoscopy 423 Applications 446

Interventions during surgery to prevent Prevention 446
postoperative pain 423 Research 447
Epidural analgesia 425 Treatment 447
Oxycodone 425 Summary-conclusion 448
Oxycodone central nervous penetration 427 Applications to other areas 448
Epidural oxycodone 428 Mini-dictionary of terms 448
Applications to other areas 428 Key facts 448
Other agents of interest 429 Conflict of interest 448
Mini-dictionary of terms 429 References 448
Key facts of epidural oxycodone 430
Summary points 430 41. Pain-related behavioral scales
References 430 among a low back pain population:
A narrative review
39. Levobupivacaine features and
Dalyah Alamam
linking in infiltrating analgesia
Introduction 451
D. Bagatin, T. Bagatin, J. Nemrava, K. Šakic,
L. Šakic, J. Deutsch, E. Isomura, M. Mali
c, Methodology 452
M. Šarec Ivelj, and Z. Kljaji
c Results 452
Discussion 453
Pharmacological basis for choice of local
Limitations 457
anesthetic for central and peripheral
Conclusions 457
blocks 433
Clinical implication/Applications to other
Local anesthetic properties 434
areas 457
The mechanism of LA action 434
Pharmacokinetics 435
Key facts 458
Absorption 435
Summary points 458
Distribution, biotransformation, and
Appendix 458
excretion 436
References 459
Local anesthetic toxicity 436
Pharmacology and use of levobupivacaine 437
42. The analgesia nociception index:
Our local infiltration analgesia (LIA) body
protocol 438
Features and application
Discussion 438 Sonia Bansal and Kamath Sriganesh
Conclusions 439
Introduction 463
Basic principle of the ANI 464
Other agents of interest 440
Features of the ANI monitor 465
Interpretation of ANI values 466
Key facts of levobupivacaine 441
Clinical applications 467
Summary points 441
Detection of intraoperative nociception 467
References 442
Postoperative pain assessment 468
Pain assessment in pediatric patients 469
Pain assessment in ICU setting 469
Part IV Effect on opioid consumption 469
Assessments, screening, and resources Comparison with other objective analgesia/
nociception monitors 470
40. The pain catastrophizing scale: Confounders for ANI 470
Features and applications Conclusions 470
Turgay Tuna
Key facts of ANI 471
Introduction 445 Summary points 471
Features 446 References 471
xvi Contents
43. Pain, anesthetics and analgesics/ Physiological and pathological aging:

back pain evaluation Cognitive impairment 494
questionnaires Biology of aging 494
Biology of pain 495
Jun Komatsu Pain in the elderly 496
Introduction 475 Neurodegenerative disorders: Alzheimer’s
Back pain evaluation questionnaires for disease 496
disease-specific measures 476 Pain and Alzheimer’s disease 497
Oswestry disability index (ODI) 476 Pain in the elderly with advanced dementia 498
Roland-Morris disability questionnaire Future 502
(RMQ) 476 References 504
Japanese Orthopaedic Association (JOA)
score for diseases with LBP 476 46. Biomarkers in endometriosis-
Japanese Orthopaedic Association back associated pain
pain evaluation questionnaire Deborah Margatho and Luis Bahamondes
(JOABPEQ) 476
Conclusion 478 Background 507
Suggestions for practical procedures 481 Prevalence 509
Applications to other areas 481 Diagnosis 509
Other agents of interest 481 Classification 509
Comprehensive measure of general health Treatment 510
status 481 Biomarkers 510
Psychiatric problems measure in orthopedic Blood biomarkers 510
patients 482 Biomarkers of angiogenesis, growth factors,
Mini-dictionary of terms 482 and growth factor receptors 510
Key facts 482 Apoptosis markers 511
Summary points 484 Cell adhesion molecules and other
References 484 matrix-related proteins 511
Cytoskeleton molecules 511
44. The back pain functional scale: Molecules involved in DNA repair/telomere
Features and applications maintenance 511
High-throughput molecular markers 511
Meltem Koç and Kılıçhan Bayar Hormonal markers 511
Introduction 487 Immune system and inflammatory
Applications to other areas 489 biomarkers 511
Other agents of interest 489 Oxidative stress markers 518
Mini-dictionary of terms 490 Posttranscriptional regulators of gene
Key facts of back pain functional scale 490 expression 518
Summary points 490 Tumor markers 518
References 490 Urine biomarkers 518
Endometrial biomarkers 518
45. Cognitive impairment, pain, and Angiogenesis and growth factors/cell
adhesion molecules/DNA repair
analgesia
molecules/endometrial and mitochondrial
Vanesa Cantón-Habas, proteome/posttranscriptional regulators of
Jos
e Manuel Martı́nez-Martos, gene expression 519
Manuel Rich-Ruiz, Marı́a Jesús Ramirez- Hormonal markers 519

Exposito, and Marı́a del Pilar Carrera-González
Inflammatory and myogenic markers 520
Introduction 493 Neural markers 520
Applications to other areas 493 Tumor markers 520
Mini-dictionary of terms 494 Discussion 522
Key facts 494 Mini-dictionary of terms 523
Contents xvii
Key facts of endometriosis 523 SAMS biomarkers 541

Summary points 523 Creatine 542
Applications to other areas 523 Lactic acid 542
References 523 Creatinine 542
Troponin 542
47. Biomarkers in bladder pain Myoglobin 543
syndrome: A new narrative Fatty acid-binding proteins 543
Coenzyme Q10 (CoQ10) 543
Thais F. de Magalhaes and Jorge Haddad Enzymes 543
Introduction 527 Urinary biomarkers 545
Challenges in IC/BPS knowledge 528 Micro RNA 545
Biomarkers 528 Conclusion 545
Bladder wall biopsy specimens 531 Other agents of interest 545
Urine 532 Applications to other areas 546
Serum 532 Mini-dictionary of terms 546
Stool 532 Key facts 546
IC/BPS biomarkers and their potential Summary points 547
relationship to disease pathophysiology 532 References 547
NGF 532
Inflammatory and angiogenic markers 533 49. Performance-based and
APF and HB-EGF 533 self-reported physical fitness
Etio-S 533 in musculoskeletal pain
Urothelial dysfunction 533
Cristina Maestre-Cascales,
GP51 534
Javier Courel-Ibáñez, and
Microbiome 534 Fernando Estevez-López
Other agents of interest 534 Physical fitness 551
Mini-dictionary of terms 535 Musculoskeletal disorders 551
Key facts 535 Widespread musculoskeletal pain 552
Key facts of biomarkers in bladder pain Assessment of physical fitness in
syndrome 535 widespread musculoskeletal pain 552
Summary points 535 Applications to other areas 552
References 535 Other agents of interest 557
48. Biomarkers of statin-induced Key facts 559
Summary points 559
musculoskeletal pain: Vitamin D
References 559
and beyond
Michele Malaguarnera Index 563
Introduction 539
Statin associated muscle symptoms 539
Cholesterol and vitamin D 541
Contributors
Numbers in parenthesis indicate the pages on which the authors’ Kılıçhan Bayar (487), Department of Physiotherapy and
contributions begin. Rehabilitation, Faculty of Health Sciences, Mu
gla Sıtkı
Dalyah Alamam (451), Physiotherapy, Health Rehabili- Koçman University, Mugla, Turkey
tation Sciences Department, Collage of Applied Mustafa Suat Bolat (353), Department of Urology, Gazi
Medical Sciences, King Saud University, Riyadh, Saudi State Hospital, Samsun, Turkey
Arabia; Arthritis and Musculoskeletal Research Group,
Luiz Guilherme S. Branco (201), Department of Basic and
Sydney School of Health Sciences, Faculty of Medicine Oral Biology, School of Dentistry of Ribeirao Preto,
and Health, The University of Sydney, NSW, Australia
University of Sao Paulo, Sao Paulo, Brazil
Amanda Spring de Almeida (247), Graduate Program in
R.B. Brandt (93), Department of Neurology, Leiden Uni-
Pharmacology, Federal University of Santa Maria
versity Medical Center, Leiden, The Netherlands
(UFSM), Santa Maria, RS, Brazil
Robert (Trey) H. Burch III (373), Department of Anesthe-
Gulbin Tore Altun (391, 405), Memorial Health Group,
siology, Walter Reed National Military Medical Center,
Department of Anesthesiology and Reanimation,
Bethesda, MD, United States
Istanbul, Turkey
Recep B€ ukalpelli (353), Department of Urology, Ondo-
uy€
Reyhan Arslantas (381), Department of Anesthesiology
kuzmayıs University, Samsun, Turkey
and Reanimation, Taksim Training and Research Hos-
pital, Istanbul, Turkey Vanesa Cantón-Habas (493), Department of Nursing,
Pharmacology and Physiotherapy, Faculty of Medicine
Ramazan Aşcı (353), Department of Urology, Ondo-
and Nursing, University of Córdoba; Maimónides
kuzmayıs University, Samsun, Turkey
Institute for Biomedical Research (IMIBIC), University
D. Bagatin (433), Polyclinic Bagatin, Department of of Córdoba, Reina Sofia University Hospital, Córdoba,
Surgery and Anestesiology with Ranimatology, Zagreb, Spain
Split; Faculty of Dental Medicine and Health Osijek,
Mehmet Canturk (37), Department of Anesthesiology and
Department of Surgery and Anestesiology With Reani-
Reanimation, Karadeniz Eregli Government Hospital,
matology, Depatment of Dental Medicine 1, Univeristy
Eregli, Turkey
Josip Juraj Strossmayer, Osijek, Croatia
Marı́a del Pilar Carrera-González (493), Department of
T. Bagatin (433), Polyclinic Bagatin, Department of
Nursing, Pharmacology and Physiotherapy, Faculty of
Surgery and Anestesiology with Ranimatology, Zagreb,
Medicine and Nursing, University of Córdoba; Mai-
Split; Faculty of Dental Medicine and Health Osijek,
mónides Institute for Biomedical Research (IMIBIC),
University of Córdoba, Reina Sofia University Hospital,
Córdoba; Experimental and Clinical Physiopathology
Research Group, Department of Health Sciences,
Luis Bahamondes (507), Department of Obstetrics and Faculty of Experimental and Health Sciences, Uni-
Gynaecology, University of Campinas Medical School, versity of Jaen, Jaen, Spain
Campinas, SP, Brazil
U.G. Chandrika (47), Department of Biochemistry,
Sonia Bansal (463), Department of Neuroanaesthesia and Faculty of Medical Sciences, University of Sri Jayewar-
Neurocritical Care, National Institute of Mental Health denepura, Nugeggoda, Sri Lanka
and Neurosciences, Bengaluru, India
Mengmeng Chen (79), Department of Anesthesiology and
Ariel Baria (225), Los Angeles, CA, United States Perioperative Medicine, The Second Affiliated Hospital
Ali Batur (Furkan) (353), Department of Urology, Selçuk and Yuying Children’s Hospital of Wenzhou Medical
University, Konya, Turkey University, Wenzhou, China
xix
xx Contributors
€
Onder Cinar (353), Department of Urology, B€ulent Ecevit Deni Francesco (69), Department of Anesthesia and
University, Zonguldak, Turkey Intensive Care, IRCCS Ospedale San Raffaele, Milano,
Marilaeta Cindryani (343), Department of Anesthesi- Italy
ology and Intensive Care, Sanglah Hospital, Faculty R. Fronczek (93), Department of Neurology, Leiden Uni-
of Medicine, Udayana University, Denpasar, Bali, versity Medical Center, Leiden, The Netherlands
Indonesia Alfonso Gil-Martı́nez (105), Department of
Arron M. Cole (257), Department of Otolaryngology— Physiotherapy, Health Sciences Faculty, University of
Head and Neck Surgery, NewYork-Presbyterian Hos- La Salle Madrid; Unit or Division of Physiotherapy,
pital, New York, NY, United States Hospital La Paz Institute for Health Research, Madrid,
Javier Courel-Ibáñez (551), Department of Physical Spain
Activity and Sport, University of Murcia, San Javier, J. Haan (93), Department of Neurology, Leiden University
Spain Medical Center, Leiden; Department of Neurology,
Carlos Cruz-Montecinos (275), Department of Physical Alrijne Hospital, Leiderdorp, The Netherlands
Therapy, Faculty of Medicine, University of Chile, Jorge Haddad (527), Urogynecology Division, Discipline
Santiago, Chile; Department of Physiotherapy, Physio- of Gynecology, Clinics Hospital at University of
therapy in Motion Multispeciality Research Group Sao Paulo, Sao Paulo, SP, Brazil
(PTinMOTION), University of Valencia, Valencia, Spain Alberto Marcos Heredia-Rizo (291), Department of
Dmitry M. Davydov (211), University of Jaen Hospital, Physiotherapy, Faculty of Nursing, Physiotherapy and

Jaen, Spain; Wyzsza Szkoła Społeczno-Przyrodnicza Podiatry, University of Seville, Seville, Spain
im. Wincentego Pola w Lublinie / Vincent Pol Munetaka Hirose (235), Department of Anesthesiology
University in Lublin, Poland; Laboratory of Neuroim- and Pain Medicine, Hyogo College of Medicine, Nishi-
munopathology, Institute of General Pathology and nomiya, Hyogo, Japan
Pathophysiology, Russian Academy of Sciences,
Moscow, Russia Che Aishah Nazariah Ismail (139), Department of Phys-
iology, School of Medical Sciences, Health Campus,
J. Deutsch (433), Polyclinic Bagatin, Department of Universiti Sains Malaysia, Kota Bharu, Kelantan,
Surgery and Anestesiology with Ranimatology, Zagreb, Malaysia
Split, Croatia
E. Isomura (433), Polyclinic Bagatin, Department of
John W. Devlin (57), Department of Pharmacy and Health
Surgery and Anestesiology with Ranimatology, Zagreb,
Systems Sciences, Bouve College of Health Sciences, Split, Croatia
Northeastern University; Division of Pulmonary and
Critical Care Medicine, Brigham and Women’s Hos- A.A. Gde Putra Semara Jaya (343), Department of Anes-
pital, Boston, MA, United States thesiology and Intensive Care, Mangusada Hospital,
Faculty of Medicine, Udayana University, Badung,
Javier Dı́az de Terán (105), Department of Neurology;
Bali, Indonesia
Unit or Division of Physiotherapy, Hospital La Paz
Institute for Health Research, Madrid, Spain Asad Jehangir (173), Gastroenterology Section,
Department of Medicine, Temple University School
Pelin Corman Dincer (163), Department of Anesthesi-
of Medicine, Philadelphia, PA; Gastroenterology
ology and Reanimation, School of Medicine, Marmara
Section, Medical College of Georgia at Augusta
University, Istanbul, Turkey
University, Augusta, GA, United States
Fernando Estevez-López (551), Department of Pediatrics,
Wilhelmina Children’s Hospital, University Medical Ureshani Karunarathna (47), Department of Pharmacy
Center Utrecht, Utrecht, The Netherlands and Pharmaceutical Sciences, Faculty of Allied Health
Sciences, University of Sri Jayewardenepura,
Alessandro Failo (15), Department of Psychology and Nugeggoda, Sri Lanka
Cognitive Sciences, University of Trento, Rovereto,
Italy Hardeep Kaur (265), Department of Pediatrics, Division
of Pediatric Pulmonology and Intensive Care, All India
Hamid Reza Fallahi (363), Dental Research Center,
Institute of Medical Sciences, New Delhi, India
Research Institute of Dental Sciences, Shahid Beheshti
University of Medical Sciences, Tehran; Founder and Seied Omid Keyhan (363), Founder and Director of Max-
Director of Maxillofacial Surgery and Implantology illofacial Surgery and Implantology and Biomaterial
and Biomaterial Research Foundation (www.maxil- Research Foundation (www.maxillogram.com),
logram.com), Isfahan, Iran Isfahan, Iran
Contributors xxi
Matthew Kim (257), Department of Otolaryngology— M. Malic (433), Polyclinic Bagatin, Department of Surgery
Head and Neck Surgery, Westchester Medical Center, and Anestesiology with Ranimatology, Zagreb, Split,
Valhalla, NY, United States Croatia
Z. Kljajic (433), Polyclinic Bagatin, Department of Zubair Malik (173), Gastroenterology Section,
Surgery and Anestesiology with Ranimatology, Zagreb, Department of Medicine, Temple University School
Split, Croatia of Medicine, Philadelphia, PA, United States
Meltem Koç (487), Department of Physiotherapy and Deborah Margatho (507), Department of Obstetrics and
Rehabilitation, Faculty of Health Sciences, Mugla Sıtkı Gynaecology, University of Campinas Medical School,
Koçman University, Mu gla, Turkey Campinas, SP, Brazil
Hannu Kokki (421), Department of Anaesthesiology and Marmiere Marilena (69), Department of Anesthesia and
Intensive Care, Kuopio University Hospital; Faculty Intensive Care, IRCCS Ospedale San Raffaele, Milano,
of Health Sciences, Clinical Medicine, University of Italy
Eastern Finland, Kuopio, Finland Jose Manuel Martı́nez-Martos (493), Experimental and
Merja Kokki (421), Department of Anaesthesiology and Clinical Physiopathology Research Group, Department
Intensive Care, Kuopio University Hospital; Faculty of Health Sciences, Faculty of Experimental and Health
of Health Sciences, Clinical Medicine, University of Sciences, University of Jaen, Jaen, Spain
Eastern Finland, Kuopio, Finland Liciane Fernandes Medeiros (149), Postgraduate Program
Jun Komatsu (475), Department of Medicine for Motor in Health and Human Development, University La
Organs, Juntendo University Graduate School of Med- Salle, Canoas, RS, Brazil
icine; Department of Orthopaedic Surgery, Juntendo Derek M. Miletich (117, 127), CDR, MC, Department of
Tokyo Koto Geriatric Medical Center, Tokyo, Japan Anesthesiology and Pain Medicine, Naval Medical
Antoine Lemaire (3), Pain and Palliative Medicine, Head Center San Diego, San Diego, CA, United States
of Oncology and Medical Specialties Department, Etienne Mullet (305), Department of Ethics, Institute of
Valenciennes General Hospital, Valenciennes, France Advanced Studies (EPHE), Plaisance, France
Nancy Liu (225), Los Angeles, CA, United States Lynita Mullins (117, 127), CDR, MC, Department of Pain
Idris Long (139), Biomedicine programme, School of Medicine, Naval Medical Center Camp Lejeune, NC,
Health Sciences, Health Campus, Universiti Sains United States
Malaysia, Kubang Kerian, Kelantan, Malaysia Glauce Crivelaro Nascimento (201), Department of Basic
Bettega Costa Lopes (149), Postgraduate Program in Phys- and Oral Biology, School of Dentistry of Ribeirao Preto,
iology, Federal University of Rio Grande do Sul, University of Sao Paulo, Sao Paulo, Brazil
Porto Alegre, RS, Brazil J. Nemrava (433), Polyclinic Bagatin, Department of
Beretta Luigi (69), Department of Anesthesia and Surgery and Anestesiology with Ranimatology, Zagreb,
Intensive Care, IRCCS Ospedale San Raffaele, Milano, Split; Faculty of Dental Medicine and Health Osijek,
Italy Department of Surgery and Anestesiology With Reani-
Pascal Madeleine (291), Sport Sciences—Performance matology, Depatment of Dental Medicine 1, Univeristy
and Technology, Department of Health Science and Josip Juraj Strossmayer, Osijek, Croatia
Technology, Aalborg University, Aalborg, Denmark Kelsey Ng (27), Hong Kong
Cristina Maestre-Cascales (551), LFE Research Group, Hisao Nishijo (317), System Emotional Science, Faculty of
Department of Health and Human Performance, Poly- Medicine, University of Toyama, Toyama, Japan
technic University of Madrid, Madrid, Spain
Rodrigo Núñez-Cortes (275), Department of Physical
Thais F. de Magalhaes (527), Urogynecology Division, Therapy, Faculty of Medicine, University of Chile, San-
Discipline of Gynecology, Clinics Hospital at Uni- tiago, Chile; Department of Physiotherapy, Physio-
versity of Sao Paulo, Sao Paulo, SP, Brazil therapy in Motion Multispeciality Research Group
Gaurav Mahajan (265), Department of Gastroenterology, (PTinMOTION), University of Valencia, Valencia,
Postgraduate Institute of Medical Sciences and Spain
Research, Chandigarh, India Adeolu Oladunjoye (173), Division of Medical Critical
Michele Malaguarnera (539), Research Centre “The Care, Boston Children’s Hospital, Boston, MA, United
Great Senescence”, University of Catania, Catania, Italy States
xxii Contributors
Olubunmi Oladunjoye (173), Department of Medicine, Experimental and Health Sciences, University of Jaen,
Reading Hospital-Tower Health System, Reading, PA, Jaen, Spain
United States Roya Sabzian (363), Dental Students Research Center,
Taketoshi Ono (317), System Emotional Science, Faculty School of Dentistry, Isfahan University of Medical Sci-
of Medicine, University of Toyama, Toyama, Japan ences, Isfahan, Iran
Antonella Paladini (329), Department MESVA, Uni- Shigekazu Sakai (317), System Emotional Science,
versity of L’Aquila, L’Aquila, Italy Faculty of Medicine, University of Toyama, Toyama,
Sanjog Pangarkar (225), Los Angeles, CA, United States Japan
Henry P. Parkman (173), Gastroenterology Section, K. Šakic (433), Polyclinic Bagatin, Department of Surgery
Department of Medicine, Temple University School and Anestesiology with Ranimatology, Zagreb, Split;
of Medicine, Philadelphia, PA, United States Faculty of Dental Medicine and Health Osijek,
Sofı́a Perez-Alenda (275), Department of Physiotherapy,
Physiotherapy in Motion Multispeciality Research
Group (PTinMOTION), University of Valencia,
Valencia, Spain L. Šakic (433), Faculty of Dental Medicine and Health
C. Ryan Phillips (117, 127), CDR, MC, Department of Osijek, Department of Surgery and Anestesiology With
Anesthesiology and Pain Medicine, Naval Medical Reanimatology, Depatment of Dental Medicine 1, Uni-
Center San Diego, San Diego, CA, United States veristy Josip Juraj Strossmayer, Osijek, Croatia
Paula Pino Pommer (275), Traumatology Department, Giorgia Saltelli (329), Sant’Andrea Hospital, “La
Hospital Clı́nico La Florida, Santiago, Chile Sapienza” University of Roma, Roma, Italy
Marcos Prada-Arias (189), Department of Pediatric Bruna Maitan Santos (201), Department of Physiology,
Surgery, Vigo University Hospital Álvaro Cunqueiro, School of Medicine of Ribeirão Preto, University of
Vigo, Spain Rare Diseases and Pediatric Medicine Sao Paulo, Sao Paulo, Brazil
Research Group, Galician Sur Health Research Institute, M. Šarec Ivelj (433), Polyclinic Bagatin, Department of
Carretera Clara Campoamor, Vigo, Spain Surgery and Anestesiology with Ranimatology, Zagreb,
Sara Pullen (285), Department of Rehabilitation Medicine, Split; Faculty of Dental Medicine and Health Osijek,
Emory University School of Medicine, Atlanta, GA, Department of Surgery and Anestesiology With Reani-
United States matology, Depatment of Dental Medicine 1, Univeristy
Anam Qureshi (173), Department of Medicine, Reading
Hospital-Tower Health System, Reading, PA; Anthony P. Sclafani (257), Department of Otolaryn-
Department of Medicine, Medical College of Georgia gology—Head and Neck Surgery, Weill Cornell
at Augusta University, Augusta, GA, United States Medical College, New York, NY, United States

Marı́a Jesús Ramirez-Exposito (493), Experimental and Tjokorda Gde Agung Senapathi (343), Department of
Clinical Physiopathology Research Group, Department Anesthesiology and Intensive Care, Sanglah Hospital,
of Health Sciences, Faculty of Experimental and Health Faculty of Medicine, Udayana University, Denpasar,
Sciences, University of Jaen, Jaen, Spain Bali, Indonesia
Martina Rekatsina (329), Chronic Pain Clinical Fellow, Wangning ShangGuan (79), Department of Anesthesi-
Whipps Cross University Hospital, Barts Health NHS ology and Perioperative Medicine, The Second Affil-
Trust, London, United Kingdom iated Hospital and Yuying Children’s Hospital of
Meani Renato (69), Department of Anesthesia and Wenzhou Medical University, Wenzhou, China
Intensive Care, IRCCS Ospedale San Raffaele, Milano, Andre Shomorony (257), Department of Otolaryn-
Italy gology—Head and Neck Surgery, NewYork-
Manuel Rich-Ruiz (493), Department of Nursing, Pharma- Presbyterian Hospital, New York, NY, United States
cology and Physiotherapy, Faculty of Medicine and Paul Clay Sorum (305), Department of Internal Medicine
Nursing, University of Córdoba; Maimónides Institute and Pediatrics, Albany Medical College, Albany, NY,
for Biomedical Research (IMIBIC), University of United States
Córdoba, Reina Sofia University Hospital, Córdoba; Kamath Sriganesh (463), Department of Neuroa-
Experimental and Clinical Physiopathology Research naesthesia and Neurocritical Care, National Institute
Group, Department of Health Sciences, Faculty of of Mental Health and Neurosciences, Bengaluru, India
Contributors xxiii
Turi Stefano (69), Department of Anesthesia and Intensive Gabriela Trevisan (247), Graduate Program in Pharma-
Care, IRCCS Ospedale San Raffaele, Milano, Italy cology, Federal University of Santa Maria (UFSM),
Dirson João Stein (149), Postgraduate Program in Medical Santa Maria, RS, Brazil
Sciences, Federal University of Rio Grande do Sul, Turgay Tuna (445), University Hospital Erasme, Free Uni-
Porto Alegre, RS, Brazil versity of Brussels, Anderlecht, Belgium
Grace P.Y. Szeto (291), School of Medical and Health Sci- Susumu Urakawa (317), Department of Musculoskeletal
ences, Tung Wah College, Hong Kong, China Functional Research and Regeneration, Graduate
Paul M. Szumita (57), Department of Pharmacy, Brigham School of Biomedical and Health Sciences, Hiroshima
and Women’s Hospital, Boston, MA, United States University, Hiroshima, Japan
Kouichi Takamoto (317), System Emotional Science, Giustino Varrassi (329), Paolo Procacci Foundation,
Faculty of Medicine, University of Toyama, Toyama; Rome, Italy
Department of Sports and Health Sciences, Faculty of Felicity Veal (27), Unit for Medication Outcomes and
human sciences, University of East Asia, Yamaguchi, Research and Education, School of Pharmacy and Phar-
Japan macology, University of Tasmania, Hobart, TAS,
Claudio Tapia (275), Department of Physical Therapy, Australia
Faculty of Medicine, University of Chile, Santiago, Chile Quinn Wonders (225), Los Angeles, CA, United States
G.M. Terwindt (93), Department of Neurology, Leiden Dana Zandian (363), Dental Research Center, Research
University Medical Center, Leiden, The Netherlands Institute of Dental Sciences, Shahid Beheshti University
Iraci L.S. Torres (149), Laboratory of Pain Pharmacology of Medical Sciences, Tehran; Director of Maxillofacial
and Neuromodulation: Preclinical Research, Porto Surgery and Implantology and Biomaterial Research
Alegre, RS, Brazil Foundation(www.maxillogram.com), Isfahan, Iran
Preface
The etiology of pain is complex and multifactorial. This complexity is magnified by the use of analgesics and local or
general anesthetics. While analgesics can reduce pain, general anesthetics reduce consciousness and local anesthetics
reduce localized pain. Analgesics may be used after surgery performed under anesthesia. However, anesthesia is not
without risk. Depending on patient-related factors such as comorbid disease, anesthesia may be associated with significant
morbidity or even mortality. Adverse events during or after anesthesia may necessitate the use of other pharmacological
agents such as vasopressors, inotropes, sedatives, antiarrhythmics, or antiemetics.
The perception of pain itself results from a multifaceted interaction between illness beliefs, age, gender, time of onset,
stress, socioeconomic status, and other factors. To a certain extent, one could argue that pain itself is helpful in treating
disease. It can be considered the “sixth vital sign” as it indicates the need for assessment by a healthcare professional and the
need for clinical investigations, diagnosis, and appropriate medication. The pain associated with myocardial infarction is a
good example of this. One needs to consider though that some acute and chronic pain can lead to psychological distress and
reduced quality of life. In the long term, chronic persistent pain can impact significantly on the family unit and many
diseases present with pain. There are a plethora of pharmacological agents currently available for pain management.
Furthermore, studies showing the beneficial effects of plant or natural extracts provide the foundation for further rigorous
studies in clinical trials.
The neuroscience of pain in one condition may be relevant to understanding the pain observed in other conditions. The
onset of pain, the cause of the pain, and the administration of analgesia or anesthesia is a continuing scientific spectrum. At
each point, there is a firm scientific basis with established literature and also an ongoing drive to discover new facts and
data. Hitherto, such material on the neuroscience of pain, anesthesia, and analgesia has been sporadic and/or written for the
experts who specialize in narrow and focused areas. For example, the expert in the use of general anesthetics in the surgical
setting may not necessarily be an expert in the molecular biology of neurons activated in the pain process. The cellular
biologist may be aware of neither the science underpinning the provision of anesthesia nor the adverse outcomes that
the anesthesiologist may encounter in the clinical setting. To address the aforementioned issues, the editors have compiled
The Neuroscience of Pain, Anesthetics, and Analgesics.
The Neuroscience of Pain, Anesthetics, and Analgesics is divided into three books:
Book 1: Features and Assessments of Pain, Anesthesia, and Analgesia
Book 2: Treatments, Mechanisms, and Adverse Reactions of Anesthetics and Analgesics
Book 3: The Neurobiology, Physiology, and Psychology of Pain
This book, Features and Assessments of Pain, Anesthesia, and Analgesia, is divided into four parts. Part I, Setting the
Scene: General Aspects of Anesthesia, Analgesics, and Pain, covers topics on anesthesia and body mass, management
of pain in older people, concept of multimorphic cancer pain, and multidisciplinary acute pain service. Part II, The Syn-
dromes of Pain, covers topics on cluster headache and pain, migraine and pain, phantom limb pain, birth and pain, breast
cancer and nociception, and Carpal tunnel syndrome. Part III, Interlinking Anesthesia, Analgesics, and Pain, covers topics
on multimodal analgesia and postsurgical pain, spinal anesthesia and cesarean section, postoperative pain management and
truncal blocks in surgery, and anesthesia and combat-related extremity injury. Part IV, Assessments, Screening, and
Resources, covers topics on the Pain Behavior Scale, the Pain Catastrophizing Scale, The Analgesia Nociception Index,
Back Pain Functional Scale, and serum biomarkers for headache.
Each chapter has:
l An Abstract (published online)
l Key Facts
l Mini-Dictionary of Terms
l Applications to Other Areas
xxv
xxvi Preface
l Other Agents of Interest

l Summary Points
The section Key Facts focuses on areas of knowledge written for the novice. The Mini-Dictionary of Terms explains
terms that are frequently used in the chapter. The Applications to Other Areas describes other fields of neuroscience, pain
science, analgesia, and anesthesia that the chapter may be relevant to. The Summary Points encapsulates each chapter in a
succinct way.
The Neuroscience of Pain, Anesthetics, and Analgesics is designed for research and teaching purposes. It is suitable for
neurologists and anesthesiologists as well as those interested in pain and its interlink with pain relief. It is valuable as a
personal reference book and also for academic libraries that cover the neuroscience of pain, anesthetics, and analgesics.
Contributions are from leading national and international experts including those from world-renowned institutions.
Rajkumar Rajendram, Victor R. Preedy, Vinood B. Patel, and Colin R. Martin

(Editors)
Part I
Setting the scene: General

aspects of anesthesia, analgesics
and pain
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nobleman was upon him, and, having issued several gruff orders to
his subordinates, he led the way along a beaten trail into the hills. As
they went, Prexaspes sought information.
“How long has the Prince been at his summer house?”
“Seven days only. He has just married a new wife, the daughter of
Nebuchadezer, Prince of Nineveh, and he has taken her there, as he
says, to be at peace, leaving his other wives at the palace.”
“Has he many people with him?”
“Oh, yes! Thirty notables of Nineveh came as an escort with the new
wife. Thirty Medean nobles are with them for company. Besides,
King Crœsus is there and also the son of Hillel of Damascus. There
be the Babylonian hostages and Gaumata, the chief Magian, and a
hundred others from far and near. A thousand cavalry guard the
camp. Great games have there been! The Prince has proven himself
to be a mighty archer and spear-thrower. He outshoots them all. Well
it is for them! For the liquor—you know?”
Merobates waved his hand suggestively towards his mouth as
though quaffing from a goblet. Prexaspes nodded assent.
“How is the Prince’s temper?” he asked.
“Excellent! Never better! His new wife pleases him and his servants
have learned how to avoid crossing him. But what is this news,
which you have galloped from afar to bring?”
“It is for the Prince’s ears first; but know, O Merobates, that great
fortune either of good or evil hangs over your head and mine to-day.
How does the Prince regard himself now?”
Merobates laughed.
“He has adopted the customs of the lowlander dogs who salaam to
the earth before royalty. Cambyses has forgotten that he is mortal
and swears that he will do even greater deeds than the Great King,
his father. If you would please him, prostrate yourself and bow very
low to the earth. Were he God himself, he could not be pleased more
with adulation and homage! Praise his deeds—he swells with pride.
Fail to praise—you may as well leap from the tower in the city
market! Please him—a gold chain and a chief place at feasts is your
reward! Displease him,—a bowstring at your throat, or hanging by
your heels to a beam, or some other evil! Me has he ever
commanded to treat him as ever I have,—with respect and
obedience, but not with lying adulation. I tell him his faults. He
laughs.”
“I remember, he used to say that Merobates was his conscience and
was the only man who dared to cross him or to speak plainly to him.”
“It has always been so. He is violent. He fears not to smite in wrath;
but he is subject to persuasion and art. He has no patience with
those whom he dislikes and he dislikes all who neglect to praise him.
Even the great Belteshazzer, appointed Governor of this province by
Cyrus, has not escaped his anger. The Prince has revoked his
authority.”
Presently they entered a canyon, in which a clear brook tumbled
over rocks. Following this they soon entered a small valley. Great
trees bordered the margin of the stream and were scattered over the
valley, forming a natural park. In the midst was the Prince’s palace, a
low structure built of hewn timbers. A score of lesser houses and
many tents stood at the sides of an open field several acres in
extent, which lay in front of the palace. On this field the sports and
contests of which Cambyses was fond were held.
Prexaspes now perceived a group of men gathered beneath the
spreading branches of a great live-oak near the palace. One, who
was seated on a thronelike chair higher than the others, was
engaged in conversation with another who stood uncovered before
him and whose dress indicated that he was a priest. Others standing
near appeared to be giving close attention. He who was seated was
a large, heavy-limbed man, well-padded with fat and short-necked
and gross. His big, round head was covered with a mass of curly
black hair and was encircled by a gem-studded coronet. His face
was dark, heavy, and flaccid, but his black eyes looked forth
shrewdly from beneath overhanging brows. Bushy eyebrows met
above his beaklike nose. A heavy black beard cut to a length of
about six inches covered the lower part of his face. He was a
powerful man physically and was said to be agile and quick in spite
of his fat.
Such was Cambyses, elder son of Cyrus. There were marks of
dissipation on his face. From early youth he had indulged his
passions, until now, at the age of thirty years, he was a slave to
them.
The sound of approaching hoofs called the Prince’s attention to
Prexaspes and his followers. He paused in his discourse and
exclaimed angrily: “Who comes? It must be very important service to
cause men to ride thus into my presence!”
Prexaspes halted at twenty paces’ distance, gave the reins of his
steed to Merobates, sprang to the earth and drew near, uncovering
his head as he advanced. Cambyses then recognized him and
uttered an exclamation of surprise and pleasure. Prexaspes,
throwing himself on his face at the Prince’s feet, cried: “All hail, King
of Kings! May the Great King of all the World live forever!”
For a moment, Cambyses was silent. He knew the meaning of those
words. His face paled and he sank back upon his seat. But
recovering he said, in a voice quivering with excitement: “Rise up,
Prexaspes! What mean you? Why are you here? What of my
father?”
“I will speak only if you bid me, mighty King!”
“Speak on!”
“King Cyrus, the Great King, the immortal hero, greater than
Jemshid, greater than Kaiomur, is no more alive! But there lives a
greater, even Cambyses, King of Kings, King of the Whole Earth;
and, to him bring I this message at the command of the noble
Hystaspis, King of Iran, thy subject. May I find forgiveness as a
bearer of this evil news of the death of thy father, and favor as a
bearer of the good news of thy accession to the throne!”
Cambyses was again silent, unable fully to realize his elevation to
supreme authority. His eyes turned upon his courtiers, who forthwith
fell on their faces before him, and cried out: “All hail, King of Kings!
Live forever!”
He drew a deep inspiration. Graciously extending his hand he
motioned to Prexaspes to rise and draw near; and, taking from his
own neck a heavy gold chain, he placed it around the messenger’s
neck, saying:
“I give you my favor, noble Prexaspes! A long and weary journey
have you come to bear me this news; and you shall be rewarded.
That has come to pass which had to come. Henceforth Cambyses,
the Achæmenian, son of Cyrus, heaven-born, reigns and shall reign!
I thank you, Prexaspes! You shall have room in my palace here and
shall feast this night. On the morrow we will return to our capital and
proclaim my accession to the throne. Sit down here on my right hand
and tell me of the death of my father. There shall be proclaimed
throughout the empire forty days of mourning for my father and, after
that, forty days of rejoicing for me.”
“I am indeed weary and travel-stained,” rejoined Prexaspes, looking
down upon his dusty clothes. “I have ridden day and night, that I
might hasten to you. I pray you command that I may retire and dress
as becomes one who stands in the presence of the King.”
“Mind not the clothes! It pleases me to note such eagerness in my
service. Ho, there, cup-bearer!” cried the King, turning to a youth
who stood waiting near the palace door. “Bring cups and wine!”
Instantly the cup-bearer clapped his hands. Two servants came
running from the palace, one bearing a jar of wine, the other a tray of
golden goblets. The goblets were quickly filled with ruby wine and
the cup-bearer presented them to the King, after duly tasting them.
Cambyses took one and handed it to Prexaspes.
“Drink!” he said. “You must be thirsty. But, perhaps, my father has
trained you to soberness?”
“While King Cyrus lived I obeyed him. Now that Cambyses is King of
Kings, I obey him,” answered Prexaspes, taking the cup.
“Well said!” exclaimed Cambyses, taking a huge goblet. “Come, let
us first pour a libation to the earth and its gods.”
He poured a little of the wine out upon the earth and drank the
remainder. Prexaspes followed suit. The King laughed as he looked
around upon his courtiers and saw that their countenances were
expressive of curiosity and mild astonishment. Pouring libations to
the gods of earth was sin with the orthodox Aryans and a new
practice to the majority of those present. But they expected that
Cambyses would disregard custom and law, even more now as King
than he did while only a prince.
“Now sit here by me and briefly tell how my father died and all that
happened thereafter,” said the King to Prexaspes. “Afterwards you
shall rest.”
Prexaspes sat down at the King’s right hand on a low bench. The
courtiers and attendants, obeying a motion of the King’s hand,
retired beyond hearing.
“I thank you, O King, for this favor!” answered Prexaspes. “My last
message was written just before your father encamped with his army
on the left bank of the Jaxartes and two days before the last great
battle. It had been in the King’s mind to cross the river and pursue
the enemy farther when he learned from his scouts and some
prisoners that the Touranians were gathering at a point ten
parasangs above us with the intention of giving battle. Then the King
set his army in battle-array, in a very strong position, with the left
wing resting on the river and the right far out in shifting sand-dunes.
In front was a deep, narrow water-course beyond which lay an open
plain over which the enemy must come. He commanded the Prince
of Iran to lead the Imperial Guard to a position behind the sand-
dunes, ready to come out upon the enemy’s flank and rear when the
battle should be joined.”
The King interrupted, exclaiming: “A young man is Prince Darius to
hold so important a command! By my beard! Infants shall not
command under me!”
“Your will is law, O King,” rejoined Prexaspes bowing. “But I must say
that Prince Darius is a most loyal subject of Cambyses and a very
brave and able general. King Cyrus took position at the left of our
army and the weight of the enemy’s charge fell upon that part. It was
a fearful struggle. My light-armed troopers went out to draw the
enemy to charge and, as commanded, fell back before the
thousands on thousands of shrieking, howling foemen. They
followed us into the great ditch in our front and pressed across. They
bore back the Persian and Medean heavy-armed infantry. They
broke through and would have ruined the army, had not King Cyrus
at the head of five thousand men of the Imperial Guard thrown
himself into the breach and held them back by most mighty
exertions! Then came the Prince of Iran and the remainder of the
Guard down from the right upon the rear of the enemy, crushing and
rolling them back into the Jaxartes. His charge saved the day. It was
magnificent. The light horses of the Touranians went down like
leaves before a gust of wind. But just as the victory declared for us,
the King received a poisoned dart in his throat and was borne from
the field by the noble Otanes. In spite of all that the surgeons could
do, he died that night.”
“What message did he leave?”
“King Hystaspis was in command of the army. He called a council of
officers and designated me as a messenger to bring to you the last
decree of the Great King. Here it is.”
Prexaspes drew a packet from a pouch at his belt and presented it to
the King. Cambyses eagerly unbound it and began to read. A dark
frown slowly gathered on his face. He suddenly cast the paper upon
the earth and set his foot upon it, while his gleaming eyes showed
bitter wrath.
“What!” he exclaimed. “Does he think to divide his empire and
confirm that hair-brained, beardless Bardya as ruler of Iran and
Persia? I say, it shall not be! I am King of Kings now, and I shall reign
alone! I will cut that young sprout off if he dare claim a shadow of
sovereignty! My father always hated me and loved Bardya. He
always did shield that boy from my wrath. Now he gives him the best
part of the kingdom! What if he does acknowledge me as overlord?
Is he not ambitious? He will ingratiate himself with the people and
then will attempt to overthrow me! King Hystaspis and his son,—they
doubtless will aid him!”
He rose and paced back and forth, swinging his arms and smiting his
hands together. Prexaspes also rose and, though standing in a
humble attitude, covertly watched the King.
“What say you?” demanded Cambyses, halting before Prexaspes.
Prexaspes, after some hesitation, answered: “Doubtless it was not
just in the Great King to make such provisions; but he was old and
very fond of Prince Bardya. Why allow the decree to be published?
There is no need until you are firmly established. Afterwards there
will be time to deal with the matter.”
The King silently stroked his whiskers a moment considering the
advice. It seemed shrewd and good. His wrath cooled somewhat. A
cunning look came upon his flushed countenance.
“That is good advice, Prexaspes!” he assented. “You shall be my
chief counselor. This decree shall be burned. None know its contents
but you and I. I count on your silence and will greatly reward you. If
you deceive me, no death shall be too severe for you!”
“Have no doubt of me, Great King! I am your servant and will do as
you bid. There is no decree. I have forgotten it. Let it not be seen of
men. But Bardya has a copy of it and the Persian nobles witnessed
it.”
He recovered the paper from the earth and restored it to Cambyses.
The latter laughed as he tore it in small pieces. Calling a servant to
bring a brazier of coals, he placed the fragments upon the embers
and watched them burn.
“Hark you, Prexaspes!” he then said. “This Bardya must not be
allowed to divide this kingdom. See to it! Great will be your reward.
The second place in the kingdom shall be yours. Do you
understand?”
Prexaspes considered a moment. He well understood the meaning
Cambyses sought to convey.
“I understand,” he then said. “Perhaps misfortune will overtake the
young man. Who knows?”
The King laughed harshly. “An accident perhaps! Rather than that
the empire be divided, one of us should die. The world is not large
enough to hold two kings when Cambyses is one of them! What do
you advise?”
Prexaspes thoughtfully contemplated the earth. The King impatiently
waited, glowering at him with the restless, cruel eyes of a tiger.
“Speak!” commanded the King at length. “Shall we send a force and
take him?”
“If it please you, O King, that I should offer advice, no. Bardya is
strong in the love of the Aryan race. He now dwells in the midst of
hosts of stout men who are his friends and who would overthrow
your throne if they could for his sake. Persian and Medean soldiers
cannot be compelled to make war upon Bactrians when led by a son
of Cyrus. Babylon, Assyria, Damascus, Sardis, and the Ionian cities
will not uphold your hands; they but wait for an opportunity to rebel.
You must court the favor of the Aryan race. Above all I advise that
you show favor to the King of Iran and to his able son. They are the
idols of the veteran army of Cyrus.”
“But Darius is Bardya’s friend!”
“True, but he is also your loyal supporter.”
“How know you? Is it not said openly among the nobles of Persia
that Hystaspis by right of birth should have ruled instead of Cyrus?
Darius is ambitious. I know that youth! I have hated him since my
father showed more favor to him and to Bardya than to me! He
knows this. How then say you he will be my supporter?”
“Do you not remember his love of truth and his hatred of lies and
deception from his boyhood up?”
“I remember! No doubt it was a disease in him!”
“Just so! Nevertheless it is said throughout Persia and Iran and by
every man of the great army, that, when once the word of the Prince
of Iran is given, it will stand forever. No one ever requires of him a
witness or a written tablet. Now at the request of Cyrus and with
consent of his father, he placed his hands in those of the Great King
and swore to support you and Bardya on the throne of this empire.
Therefore you need not fear him; but, rather, you may depend upon
him for aid if you need it.”
The cloud on the King’s face lifted somewhat. He had watched with
jealous eye the growing power of the young Hystaspis and had
feared him even more than Bardya.
“Nevertheless, wait till his ambition meets opportunity,” he
suggested.
“No, it is as I say. I have proof. On the march to Bactra, the Prince
with the Imperial Guard was in charge of the transport of the King’s
body. The Guard, on the morning of the second day’s march, saluted
Darius as King of Kings; and all had taken oath to support him if he
would consent. But he rebuked them, told them of his oath to support
you, and then and there made them also swear with uplifted hands
to support you. I myself witnessed it.”
“Is it so? Treason must be flourishing indeed!” exclaimed Cambyses,
bitterly. “This Guard shall no longer be the Imperial Guard! It shall be
decimated!”
Rage again possessed the King’s soul. He knew himself to be
unpopular save with a few boon companions. His jealous heart was
filled with hatred towards the popular Prince. Prexaspes ventured to
remonstrate.
“Let not the Great King be offended with his servant! I am acquainted
with the army and all its soldiers. The Aryans are a proud race and
the nobles will not bow the knee even to their kings, as you know. Do
not anger them. Without them your subject nations will revolt and
you will have no one to support your empire. Rather, dissemble your
feelings. You are very wise, O King, if you but stop to think. First, be
well established on your throne. After the body of your heroic father
shall have been placed in its tomb, send the Prince and his Guard to
conquer new provinces. Be advised by me in this. Should evil befall
his son, old Hystaspis would lead the veterans of Cyrus five hundred
thousand strong against you. Who could stand before them?”
Cambyses ceased pacing back and forth and sat down, saying:
“Your words are wise, Prexaspes. I will be advised. Proceed!”
Prexaspes smiled slightly behind his hand. He had properly gauged
the King’s impulses. He continued: “I advise that you issue your
formal decree as King of Kings to-morrow and send copies thereof to
be proclaimed in every province of the empire; that you issue a
decree confirming the Prince of Iran in command of the Guard and in
his mission to transport the body of the Great King to Pasargadæ;
that you send a messenger to Bardya and to your sisters greeting
them kindly; that you, also, as soon as they shall have arrived at
Hamadan, show them all honor, go with them to do honor to Cyrus at
Pasargadæ, and dissemble your real feelings. Thus will you begin
wisely and thus will you please the Aryan people. Afterwards we may
take counsel; and, should Bardya meet with an accident or
disappear, who can blame the Great King? Be assured, O King, that
I advise well! I know that upon you only may I depend for
advancement and power. Bardya does not, nor do any of the great
Persian nobles, love Prexaspes. Their semi-barbaric manners suited
not my taste, and my refined manners were not approved by them!”
“I will heed your advice,” said the King. “My favor shall be with you.
First, I will make you Satrap of Medea. I will let that old Hebrew,
Belteshazzer, rest from his labors in his tower. Afterwards, if you
serve me well, I shall increase your power. See to it, Prexaspes, that
my will be not thwarted! There shall be one King, who shall be King
of Kings, and he must be Cambyses!”
“It shall be as you wish. But let us proceed with all care.” Thus
Prexaspes entered upon a road to great gain in wealth and power,
but also to ultimate woe.
The King presently dismissed Prexaspes, and the latter was
conducted to pleasant rooms in the palace, where he refreshed
himself with a bath, arrayed himself in clean linen and rich garments
and had himself barbered and perfumed by the King’s own barbers.
Cambyses was lavish with his favorites, and just now Prexaspes was
chief of them. The latter sat at the King’s right hand at dinner that
evening. All festivities were abandoned in honor of the dead King,
but the many courtiers who ate at his tables found opportunity to
assure the new King of their joy over his accession to the throne. He
drank deeply both of adulation and wine until he became half-drunk
and maudlin, whereupon Merobates took him almost forcibly to his
bedchamber.
Next day, the King and all his retinue returned to Hamadan. A royal
decree was immediately issued, reciting the death of the Great
Cyrus and the accession of Cambyses to the throne of the world,
and commanding all officers, soldiers, and peoples to acknowledge
him King of Kings. The royal treasury was opened. From it the
golden crown studded with precious gems, which Cyrus had worn on
state occasions, and the royal scepter were brought forth. Clad in
purple, and having the high, pointed crown on his head, his royal feet
encased in yellow shoes, and his hair and whiskers curled,
powdered, and perfumed, Cambyses held his first court in the great
audience room of the palace. He sat on a golden throne placed high
up on a dais, with fan-bearers waving ostrich plumes over him, with
Prexaspes standing at his right hand and Merobates at his left,
bearing the King’s sword and shield. He placed the crown on his
head with his own hands, while a loud-voiced herald recited his titles.
Then the thousand nobles and officers who were in attendance fell
on their faces to the floor before him and hailed him King of Kings,
the Great King! Cambyses, swelling with pride, deemed himself
divine, and as a god he looked down upon his subjects with haughty
demeanor.
The world thus acquired a new ruler.
CHAPTER VI
PERSEPOLIS
THE modern world knows little of the beauty and grandeur of ancient
Anshan, the home of Cyrus, or of the province of Fars and its cities.
Mountains shut off from them the hot winds of the Persian Gulf and
of the northern deserts. The high valleys lying between the mountain
ranges that extend across it like huge dikes are of surpassing
loveliness. Romantic woodlands, dells, lakes, canyons, murmuring
brooks, rushing rivers, far vistas, plains, mountains, and hills delight
the soul. In the valleys, flowers perfume the air all the year, and
vegetation, where irrigation is practiced, is luxuriant. On the high hills
and mountain tops winter holds sway during three or more months
and the seasons are well-marked as in the temperate zones. It is the
land of Omar, of Firdusi, and of many lesser poets; the land of an
ancient white race, whose rugged virtues made them lords of much
of the earth, but whose descendants have degenerated by admixture
with lower grades of humanity and have suffered much to maintain
even their own independence.
The celebrated plain of Mervdasht is between two parallel ranges of
mountains, one of which lies to the west between it and the low hot
lands of the gulf-coast and the other to the east between it and the
vale of Murghab, or ancient Anshan. A river comes down from the
northern mountains through the midst of this plain and empties into a
lake. It is a perennial stream, but fordable save in the winter when
the rains fall. It has been variously named, anciently the Araxes, later
the Kur or river of Cyrus, and again the Bendamir. Another river of
less volume but more celebrated, the Pulwar, comes down to join it
through the mountains from northeast table-lands. This passes by
the vale of Murghab, where a little stream of that name, coming from
the east, flows into it. In this vale was ancient Anshan, the capital of
the Achæmenian line of kings, a city also known as Pasargadæ. The
tortuous bed of the Pulwar connects the vale of Murghab with the
valley of Mervdasht, having cut for itself a deep gorge through the
mountains. A royal road, passing through this gorge or canyon,
connected the ancient capital with a more modern city, Persepolis.
Persepolis, or the city of the Persians, ancient Parsa, lay close to the
mouth of the mighty canyon of the Pulwar, where it opened into the
vale of Mervdasht. The city lay principally on the northern banks of
the river. On the southern bank was a great park; and in this on a
plateau extending from the base of low mountains that border the
eastern side of the plain, were the palaces of the Kings of Iran. King
Hystaspis and his great son, Darius, and his grandson, Xerxes, each
erected magnificent palaces of dark-gray marble on this natural
platform. The great size and magnificent architecture of these
buildings were among the wonders of the ancient world. Their
majestic ruins yet testify to the power, the love of art, and the
learning of those masters of men.
King Hystaspis, content to rule Iran as a nominal vassal of Cyrus and
under the shadow of his mighty arm, laid out for himself in the valley
of Merv a new city and there placed his loved friends and retainers.
He brought artisans from Egypt, Canaan, Syria, Phœnicia, and
distant Greece, and built for himself a great palace. It is said that he
or his son formulated a new alphabet for his language and caused
the books of Zoroaster to be translated therein.
Orchards of apple, peach, and apricot, vineyards where grape and
berry grew, fields of vegetables and grain, covered the fertile valley
and its surrounding hills. On the day when the Imperial Guard,
escorting the body of the Great Cyrus, halted on the summit of the
western ridge bounding the valley and looked down upon the
peaceful scene, autumn was touching all with the signs of harvest
and the coming winter-rest. On that day, while the funeral car halted,
Prince Bardya, his sisters, and the Prince of Iran rode forward to a
bluff jutting out from the ridge; and from this position they looked
down into a paradise,—so it seemed to them, weary with dusty roads
and desert lands. There, where the Pulwar entered the plain from the
narrow gorge in the western mountains, Cyrus had drawn up his
Persian patriots to fight a last battle for liberty from the Medean yoke,
having been driven to bay by the vast army of stern old Astyages, his
grandfather. That decisive battle not only gave liberty to his own
province but gave Astyages to him as a prisoner and the crown of
Medea for his own head. From that victory Cyrus had gone forth to
conquer the world. But now, conquered by the last enemy, Death, he
was returning there to his final rest. The heart of the Prince of Iran
was stirred by strong emotions, as he looked across the beautiful
vale. He could see afar the great portico of his father’s palace where,
he knew, his mother stood watching for the coming of her son.
Uncovering his head, he extended his hands towards heaven,
saying:
“To thee, O Ahura-Mazda, Ruler of Heaven, Giver of Life, Lover of
Truth, and Protector, we give thanks! For thou hast brought us
home!”
“Amen and amen!” exclaimed Bardya, uncovering his head.
The Prince of Iran then addressed his companions: “I welcome you
to the home of King Hystaspis. This valley and yonder city are his
property, ceded to him as a home for the Achæmenian family, when
he consented to remove hither from Bactra. I bid you rest at our
palace yonder this night. The road from Parsa to Anshan is rough
and ought to be traveled only by day. My mother is at the door to
welcome you.”
“We gladly accept!” assented Bardya, heartily. “Do I not love that
mother almost as much as you? Do you remember the happy days
when we hunted on yonder hills and swam in the Pulwar and the
Araxes? Do you remember the day we were almost drowned? We
will go to that deep water-hole again to-morrow and swim there as
boys again. Our troopers should rest a day while we send a
message to Cambyses at Anshan to inform him of our coming.”
Athura added: “It will be delightful to accept the hospitality of your
mother. I shall return after going to Anshan and shall stay long with
her and rest. My sister is much in need of rest. The long journey has
made her ill.”
“After we shall have accomplished our mission,” said the Prince of
Iran, “we shall enjoy many pleasant days there. The hunting is good.
We shall enjoy the royal sport!”
“Unless Ahriman interfere!” added Bardya, waving his hand towards
Anshan, where his brother now awaited their coming. “I propose to
stay a month at least. I suppose he awaits us impatiently at Anshan.”
Athura said reprovingly to her brother: “Speak not of the King of
Kings thus! He has sent us courteous messages, even if he would
not await us at Hamadan or march with us here. Perhaps it was best
that he should go on ahead to prepare the tomb and to arrange for
the ceremonies. Be advised, brother! Remember to show him the
deference due to his station. His anger was ever terrible! Now he
has no one to restrain him.”
Bardya laughed and tossed his head, as he answered: “Fear not for
me! I shall treat him with all due respect. Am I not on the ground my
father gave me in his will? The Persian lords will not permit him to
oppress us. When I see that King of Kings, I will demand of him that
he publish the full terms of my father’s will. If he refuse to observe
that—Well, it may be that he will cease to reign!”
The Prince of Iran said nothing, but his countenance was somber.
He feared that the impetuous Bardya would precipitate trouble. He
foresaw civil war.
Descending into the valley, they approached Persepolis. A vast
throng of people came out to meet them and stood on either side of
the road weeping and wailing aloud as the funeral car passed. A
company of guards led by an aged veteran met them at the entrance
of the city.
Prince Darius greeted the leader warmly: “Ho, Orobates, our beloved
High Chamberlain! How fares my royal mother?”
“All hail, Prince of Iran!” cried the stately old man, kissing the
Prince’s cheeks as the latter bent down to greet him. “God’s blessing
of long life and happiness be upon you! How good it is to behold you
once more! Your mother, our most gracious Queen, is well and
awaits you at the palace. She begs that you will prevail upon the
royal Bardya and his sisters to honor her house with their presence.
All things are prepared. The best of the herds, the finest game from
the mountains, the daintiest fruits and flowers,—all are ready!”
“They have consented to honor us, Orobates. Has my mother good
health and is she happy?”
“Excellent health, gracious Prince; but she sighs much for you and
the King.”
“Did Cambyses, the Great King, honor our house with his
presence?”
“He refused our bidding on the plea that he was in haste to reach
Anshan on state business. But he sent a gracious greeting to your
mother.”
The Prince led the caravan into the city, nodding and waving
greeting to many whom he had known when a child. Crossing the
Araxes over a magnificent stone bridge, the cortège marched into
Persepolis and encamped in a great open field on the shore of the
Pulwar. The funeral car was driven into the sacred enclosing wall of
a temple and there rested till a messenger went to Cambyses and
returned.
Leaving the cares of the encampment to subordinates, the Prince of
Iran, accompanied by Gobryas and some of his chief officers,
conducted Bardya and his sisters across the Pulwar over a beautiful
stone bridge of one great arch and through the park to his father’s
palace. The limpid stream, the great oaks, elms, walnuts, and plane
trees, whose foliage was tinged with gold and red, the flowering
shrubs, the fountains, and the greensward, smiled a joyful welcome
to the weary travelers. Broad steps, leading up to the great plateau
or bench on which the palace stood, gleamed white through the tree-
limbs. Slender gray columns adorned the portico. On the stairs stood
a group of women, and among them a stately dame, who waved her
hand in welcome. Prince Darius galloped on ahead to the foot of the
steps and, leaving his horse in charge of an attendant, ran up into
the embrace of his mother.
Age had not greatly affected the beauty of the Queen of Iran nor
dimmed her blue eyes. Her gray hair was gathered in a net at the
back of her head and was encircled by a golden band set with
sparkling gems. Her dress was an ample purple robe reaching to her
feet and encircled at the waist with a silken sash. Its loose sleeves
revealed arms still shapely and adorned with bracelets of gold. The
gracious majesty of her countenance, the sweetness of her smile,
and the soft accents of her voice were celebrated in Iran.
That was an age when wife and mother were not slaves or prisoners.
Recognized as the equal of men, their virtues and loveliness made
homes where men were grown. Not yet had Cambyses, aping the
manners and customs of the dwellers in Mesopotamia, Syria, and
Arabia, degraded women to the seclusion of harems; nor had
custom forbidden women to appear before friends unveiled, though
veils were commonly worn in public places. Polygamy was almost
unknown in Iran, though its practice had crept into Medea. The wife
was queen of the home and ruled in the heart of her husband.
The Prince knelt at his mother’s feet, and her arms encircled his
neck while her lips kissed his brow. “Welcome home, beloved son!”
she exclaimed. “Long days have intervened since you waved
farewell to me from yonder bridge; but no day has passed that I did
not think of you!”
She raised him up and stood proudly at his side, leaning on his arm,
while she welcomed Prince Bardya and his sisters. To Bardya she
said as he bent his knee before her: “The blessing of Ahura-Mazda
be upon you, O Prince of the World! Arise! It is not meet that you
kneel to me! Welcome to the palace of my lord, the King of Iran!”
“Gracious Queen,” replied Bardya as he arose, “I kneel to you as to
my mother! Next to her, who lives only in my memory, do I love and
reverence the mother of my friend, the Prince of Iran. Have we not,
in years past, stood together at your knee and received your
instruction? Now that we are indeed orphans we come to you for
consolation.”
Tears filled the great lady’s eyes. She embraced Athura and
Artistone tenderly; and, leaving the men to the care of her son, she
took the girls with her to her own apartments and personally saw that
they were made comfortable. While they are removing the dust of
the road and enrobing themselves for dinner, we may wander in
spirit through this typical palace of the Achæmenian kings and
observe its grandeur.
From the portico which extended the full breadth of the palace front,
an entrancing view of valley and mountain, of river and park, could
be had. Sixteen slender, fluted, marble pillars supported the massive
wooden roof of the portico. Their capitals were winged bulls; their
bases were bell-shaped and carved to imitate lotus buds. A high,
narrow door gave entrance from the front through the thick stone
walls into a hall, on either side of which were rooms where the
palace-guards had their abode. The hall led into a reception room
fully fifty feet square, whose walls were pierced by a dozen narrow
windows and whose ceiling of heavy carved timbers was upheld by
slender wooden pillars covered with silver plates. The stone walls
were hidden by beaten silver plates and the windows and doors
were hung with tapestries of fine crimson and purple fabrics.
Wooden shutters were fitted to the windows, but were now open to
admit air and light. Later, when winter should come with its rains and
frost, the windows would be closed by semi-transparent oiled silk.
Red and purple rugs lay on the tiled floor, partially covering the
various patterns worked out in colored tiles. A throne, shining with
gold plate, occupied a raised platform at the end of the room
opposite the entrance. Cushioned chairs, divans, and couches,
tables of polished wood, mirrors of polished silver and bronze, lamps
of many patterns fastened to the pillars and walls, and a cabinet of
dark inlaid wood comprised the furniture. The cabinet held a
collection of books, rolls, and tablets, the library and the special
treasure of the King of Iran.
Doors at the right of the throne led into the apartments of the men; at
the left, into the apartments of the women; and, immediately at the
rear, into a small open court, beyond which were the servants’
quarters. Banquets of state were held in the throne room, but
ordinarily the tables were laid in the small open court. The various
apartments were furnished with couches, and with blankets and rugs
of skillful weaving and of that fineness and texture for which the
woven products of Iran have ever been famous. All the
conveniences of an advanced civilization, which power and wealth
could provide or gather from the many nations over which the
Persians held sway, were here. Baths and toilets fed by water piped
from the hills, and drained into the Pulwar below, ornamental
cabinets, containing scents and cosmetics for adorning the person,
wardrobes full of costly dresses made of silk and fine linen, mirrors,
combs, and brushes—even the modern homes of many so-called
civilized people could boast no better.
A narrow stair led up from the inner court to the flat roof, where the
occupants of the palace, reclining on soft divans, under canopies or
sunshades, could pass the warmer hours of the day, breathe the
cool mountain air, and enjoy the lovely scenes. Looking down from it,
one could see the royal stables five hundred paces to the south in
the park, where scores of graceful horses were kept; and farther on
was the inclosure where cattle and sheep, driven in from the
mountain pastures, were ready to furnish the royal table with meat or
milk. A canal led from the Pulwar above the palace through the park
to the stables below and thence into luxuriant gardens where
servants toiled to supply their master’s table with vegetables. Fowls,
dogs, horses, and cattle enlivened the barnyard scene. Servants in
gay tunics, loose, fringed trousers, and with sandaled feet went
hither and thither on their duties. Guards in shining armor walked
their beats through the park or lazily stood leaning on their spears at
the palace steps.
While the guests were removing the dust and stains of travel,
servants busily prepared the banquet. Tables of walnut, plated with
silver and bound together by golden bands fastened with copper
nails, were set in the great audience hall. Platters of beautiful
porcelain or of beaten silver, piled high with fruits and bread, were
placed on them, and plates of silver and cups of gold were also
brought forth. Low seats whereon the guests could either sit or
recline were set in order. A major-domo in gorgeous livery saw that
all things were made ready. Then the guests were called. The men
were seated at one table; the women, at another. Prince Darius sat
at the head of the former; his mother at the head of the latter.
Servants brought on, in regular courses, fish, steaming loads of
venison and fowl, and bountiful supplies of vegetables and pastry.
Water, milk, and wine of Helbon were the drinks, the latter being
used sparingly. With appetites sharpened by a long day’s journey in
the bracing air of the mountains, the guests did full justice to the
viands. While they ate, the soft music of harps, played with
considerable skill by musicians in the court, floated in through the
open doors.
The banquet hour having passed, the officers and nobles returned to
the camp, while Prince Bardya and his sisters accompanied Prince
Darius and his mother to a room adjacent to the dining-hall, used by
the King of Iran when at home as an office. A large fireplace in one
corner of the room was filled with a cheerful blaze. Gathered about
the fire, guests and hosts felt much at home and spent a pleasant
hour in conversation.
“Now that Cambyses passed through your city with scant courtesy,”
Bardya said, somewhat warmed by the wine he had imbibed and by
his genial surroundings, so that he felt called upon to express his
indignation towards his brother, “what think you of such a king?” He
addressed Queen Hystaspis.
“I marvel not at his action,” she replied quietly. “He was never kindly
disposed towards us. But it is not for us to find fault. I should have
met him in person and given the invitation to stop with us. I would
have so done, had I not heard that he believes, with the Medes, that
women have no place in the affairs of men. He passed through our
city in a closed litter, not even deigning to see our messengers. He
made reply through his chamberlain that the King of Kings was
indisposed and pressed for time and would not rest till he should
arrive at his palace in Anshan.”
“He has ever been ill-natured!” continued Bardya, bitterly. “He
believes himself heaven-born! He will end by declaring himself a god
and appointing set times to worship him! What think you the nobles
of Persia will say of his manners? It is said he has determined to
decree a law of polygamy, and, like the Arabs, fill a harem with many

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Features and Assessments of Pain,

Anesthesia, and Analgesia 1st Edition

Manual of Equine Anesthesia and Analgesia Second

Military Advanced Regional Anesthesia and Analgesia

Cambridge IGCSE and O Level History Workbook 2C - Depth

Equine Anesthesia and Pain Management: A Color Handbook

Anesthesiology In Training Exam Review Regional

Regional Nerve Blocks in Anesthesia and Pain Therapy

Features and Management of Acute and Chronic Neuro

Unlearn Pain: The Successful Techniques And Exercises

Publisher: Nikki Levy

Typeset by STRAIVE, India

Interventional and surgical analgesic

Application to other areas 33 Mini-dictionary of terms 54

Somatosensory evoked potential and visual Prophylactic migraine treatment 108

12. Phantom limb pain Early life stress in humans including

Cannabinoids 182 Summary points 208

Psychological comorbidities and social Possible pharmacological targets for breast

Summary points 272 Low-back pain mechanisms in computer

29. Manual compression at myofascial Systemic nonopioid analgesics 334

Summary points 351 Damage control resuscitation 376

Introduction 392 Indications 409

Pain treatment after laparoscopy 423 Applications 446

43. Pain, anesthetics and analgesics/ Physiological and pathological aging:

Key facts of endometriosis 523 SAMS biomarkers 541

l Other Agents of Interest

Rajkumar Rajendram, Victor R. Preedy, Vinood B. Patel, and Colin R. Martin

Setting the scene: General

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