Pain Therapeutics

Drugs, Markets & Companies

By
Prof. K. K. Jain
MD, FRACS, FFPM

Jain PharmaBiotech
Basel, Switzerland

July 2012

A Jain PharmaBiotech Report

AUTHOR'S

BIOGRAPHY

Professor K. K. Jain is a neurologist/neurosurgeon by training and has been working in

the biotechnology/biopharmaceuticals industry for several years. He received graduate
training in both Europe and US, has held academic positions in several countries, and is a
Fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians of
UK. Currently, he is CEO and a consultant at Jain PharmaBiotech. During his active
neurosurgical career, Prof. Jain was involved in the management of pain.
Prof. Jain is also a Senior Associate Editor of MedLink Neurology, an electronic
encyclopedia of neurology published by Medlink Corporation (San Diego, California)
where he is the author in charge of writing and constantly updating the sections on
neurobiotechnology and neuropharmacology including treatment of pain.
Prof. Jain is the author of 440 publications including 21 books (4 as editor) and 50 special
reports which have covered important areas in biotechnology, gene therapy and
biopharmaceuticals. He has also written a textbook of gene therapy, which is the first
book on this subject to be translated into the Chinese language. A book on gene therapy
companies was published in 2000 by John Wiley & Sons and the updated version has
been incorporated into a report on Gene Therapy published by Jain PharmaBiotech in
2011. Prof. Jain has edited "Drug Delivery Systems" (Humana/Springer 2008, 2nd ed
2013) and Drug Delivery to the Central Nervous System (Humana/Springer 2010). His
other recent books include "Handbook of Nanomedicine" (Springer/Humana 2008;
Chinese edition, Peking University Press 2011, 2nd ed Springer 2012), Textbook of
Personalized Medicine (Springer 2009), "Handbook of Biomarkers" (Springer 2010),
"Handbook of Neuroprotection" (Springer 2011), Application of Biotechnology in
Cardiovascular Therapeutics (Springer 2011), and Application of Biotechnology in
Neurology (Springer 2012, in preparation).
The pain report is an update with inclusion of commercial information of an earlier
publication titled "Pain Therapeutics: A strategic re-evaluation" published by Reuter's
Business Insight/Datamonitor UK in 2000. Other reports written by Prof. Jain in the past
have been published by PJB Publications, D & MD, Informa, and Decision Resources Inc.
This is one of the in-house publications of Jain PharmaBiotech that are constantly
updated.

July 2012
Copyright 2012 by
Jain PharmaBiotech
Blsiring 7
CH-4057 Basel
Switzerland
Tel & Fax:
Email:
Web site:

+4161-6924461
info@pharmabiotech.ch
http://pharmabiotech.ch/

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, or otherwise without the prior written
permission of the Publisher. This report may not be lent, resold or otherwise traded in any manner without the
consent of the Publisher. While all reasonable steps have been taken to ensure the accuracy of the information
presented, the Publisher cannot accept responsibility for inadvertent errors or omissions.

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TABLE

OF

CONTENTS

0. Executive Summary .............................................................................. 17

1. Basic Aspects of Pain ............................................................................ 19
Introduction....................................................................................................................... 19
Historical aspects of pain ................................................................................................... 19
Pain definitions .................................................................................................................. 21
A glossary of terms relevant to pain .................................................................................. 22
Pain classification and description ..................................................................................... 22
Neuropathic pain.............................................................................................................. 23
Refractory neuropathic pain.......................................................................................... 24
Classification of neuropathic pain according to levels ....................................................... 24
Cancer pain ..................................................................................................................... 25
Bone pain in cancer ..................................................................................................... 27
Complex regional pain syndrome ....................................................................................... 27
Mechanisms of pain ........................................................................................................... 28
Pain pathways ................................................................................................................. 28
Role of nociceptors in pain transmission ......................................................................... 30
Gate control and neuromatrix theories of pain ..................................................................... 30
Pain mediators................................................................................................................. 31
Modulation of pain by pictures associated with social contacts ............................................... 32
Modulation of pain by emotions ......................................................................................... 32
Role of the sympathetic nervous system in pain ................................................................... 32
Visceral pain.................................................................................................................... 32
Pathomechanism of visceral pain................................................................................... 33
Pathomechanism of neuropathic pain.................................................................................. 33
Role of intact nerve fibers in neuropathic pain ................................................................ 33
Chemokines as mediators of neuropathic pain ................................................................ 33
Chemotherapy-induced neuropathic pain ....................................................................... 34
CNS innate immunity and neuropathic pain .................................................................... 34
Cytokines as mediators of neuropathic pain .................................................................... 34
Free radicals in generation of neuropathic pain ............................................................... 35
GABA deficiency in neuropathic pain .............................................................................. 35
Genetic basis of neuropathic pain .................................................................................. 35
Gene expression changes in neuropathic pain ................................................................. 35
Glial activation and neuropathic pain ............................................................................. 36
Immune cell-derived opioids and neuropathic pain .......................................................... 37
Spinal leptin and neuropathic pain................................................................................. 37
Tetrahydrobiopterin regulates neuropathic pain sensitivity ............................................... 37
Pathomechanism of migraine ............................................................................................. 37
Role of the immune system in pain .................................................................................... 38
Pain and itch ................................................................................................................... 38
Pathomechanism of itch ............................................................................................... 39
Clinical aspects of itch ................................................................................................. 39
Molecular pathophysiology of pain ...................................................................................... 40
Role of ion channels in pain ............................................................................................... 40
Acid-sensing ion channels ............................................................................................ 40
Calcium channels in pain .............................................................................................. 41
P2X3 ion channels ....................................................................................................... 41
Potassium ion channels ................................................................................................ 42
Sodium ion channels in pain ......................................................................................... 42
TRP ion channels in pain .............................................................................................. 43
Genetic basis of pain ........................................................................................................ 44
Study of genes in pain ................................................................................................. 45
Pain as a channelopathy .............................................................................................. 45
Pain in the brain .............................................................................................................. 46
Neuropathic pain-induced morphological changes in the brain........................................... 46
Change from acute to chronic pain ..................................................................................... 46
Descending facilitatory modulation of pain ..................................................................... 47
Development of chronic pain following severe accidental injury ......................................... 47
Pain and transcriptional repressor DREAM ...................................................................... 48
Role of neuronal plasticity in pain .................................................................................. 48
Neurochemistry of pain ..................................................................................................... 48
Molecular elements of pain in the peripheral nervous system ............................................ 48
Molecular elements of pain in the central nervous system ................................................ 49
Opioid receptors ......................................................................................................... 50
Role of AMPA receptors in chronic pain .......................................................................... 50
Kinins ........................................................................................................................ 50
Serotonin ................................................................................................................... 51

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Substance P ............................................................................................................... 51
Excitatory amino acids ................................................................................................. 51
Role of nitric oxide in pain ............................................................................................ 52
Prostaglandins ............................................................................................................ 52
Endocannabinoids ....................................................................................................... 53
Protein kinase C .......................................................................................................... 53
Adenosine and adenosine receptors ............................................................................... 54
Vitamin D and pain ...................................................................................................... 54
Vanilloid receptor ........................................................................................................ 54
TRPA1 and TRP V1 receptors ............................................................................................ 54
Endothelin-B receptors ................................................................................................ 56
Nerve growth factor and pain ....................................................................................... 56
Adrenomedullin as a pain-related peptide....................................................................... 56
Biomarkers of pain ........................................................................................................... 56
Biomarkers of visceral pain .......................................................................................... 57

2. Assessment of Pain and Analgesics ...................................................... 59

Introduction....................................................................................................................... 59
Animal models of pain ....................................................................................................... 59
An overview .................................................................................................................... 59
Selection of animal species as models for pain ..................................................................... 59
Types of noxious stimuli ................................................................................................... 60
Animal models of neuropathic pain ..................................................................................... 60
Animal models of arthritis ................................................................................................. 60
Animal models of peripheral neuropathy ............................................................................. 61
Limitations of current pain models ..................................................................................... 61
Biogenic animal model of chronic pain ................................................................................ 62
Ethical issues concerning animal pain models ...................................................................... 62
Medical evaluation of pain ................................................................................................. 63
Chronic pain as a manifestation of various diseases.............................................................. 63
Assessment of pain patients .............................................................................................. 63
Medical examination ......................................................................................................... 63
Measurement of pain ........................................................................................................ 64
Quantitative sensory testing .............................................................................................. 65
Pain measurement tools for neonates and children ............................................................... 66
Quantitative sensory testing .............................................................................................. 66
Psychological assessment of pain ....................................................................................... 67
Brain imaging in pain........................................................................................................ 67
PET for study of pain ................................................................................................... 67
PET correlated with fMRI and evoked potentials .............................................................. 68
Patient outcomes and quality of life during treatment for chronic pain .................................... 68
Collection and analysis of data on pain patients ................................................................... 69
Evaluation of analgesics in humans ................................................................................... 69
Early phase clinical trials of analgesics in humans ................................................................ 69
Design of clinical trials for pain .......................................................................................... 70
Assessment of neuropathic pain ......................................................................................... 71
Transdermal electrical stimulation for study of chronic pain ................................................... 71
Placebo effect in pain ....................................................................................................... 72
Role of electronic pain recording in determination of the placebo effect ................................... 72
Outcome measures for chronic pain trials ............................................................................ 72
Pain, pain therapies and cognitive function .......................................................................... 73

3. Pharmacotherapy of Pain...................................................................... 75
Introduction....................................................................................................................... 75
Mechanism of action of currently used pain medications ................................................... 75
Non-steroidal antiinflammatory drugs ............................................................................... 76
COX-2 inhibitors .............................................................................................................. 76
Celecoxib ................................................................................................................... 77
Metamizole ................................................................................................................. 78
Nimesulide ................................................................................................................. 78
Rofecoxib ................................................................................................................... 78
Valdecoxib ................................................................................................................. 79
Lumiracoxib ............................................................................................................... 79
Side effects of COX inhibitors........................................................................................ 80
Innovative COX-2 inhibitors in development ................................................................... 81
Acetaminophen ................................................................................................................ 82
Antioxidants as analgesics ................................................................................................. 82
Opiates and opioids ........................................................................................................... 83
Innovations in opioid therapy ............................................................................................ 83
Oral transmucosal fentanyl ........................................................................................... 84
Use of opioids for chronic non-cancer pain ..................................................................... 84

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Opioid receptor modulation for visceral pain ........................................................................ 84

Opiorphin ........................................................................................................................ 85
N-methyl-D-aspartate receptor antagonists ...................................................................... 85
Ketamine ........................................................................................................................ 85
CNS 5161 ....................................................................................................................... 86
Triptans for treatment of non-migrainous pain .................................................................. 86
Capsaicin ........................................................................................................................... 86
NGX-4010 ....................................................................................................................... 87
Local anesthetics ............................................................................................................... 87
Topical application ........................................................................................................... 87
Nerve blocks ................................................................................................................... 87
Injection of local anesthetics for analgesia ..................................................................... 88
Ultrasound-guided nerve blocks .................................................................................... 88
Topical salicylates for the treatment of pain ...................................................................... 88
Topical rubefacients for acute and chronic pain in adults .................................................. 88
Adjunctive analgesics ........................................................................................................ 89
Antidepressants ............................................................................................................... 89
Mechanism of analgesic action of antidepressants ........................................................... 90
Antiepileptic drugs ........................................................................................................... 91
Mechanism of action of antiepileptic drugs in neuropathic pain .......................................... 91
Carbamazepine ........................................................................................................... 92
Gabapentin ................................................................................................................ 92
Lamotrigine ................................................................................................................ 93
Phenytoin ................................................................................................................... 93
Pregabalin .................................................................................................................. 94
Topiramate................................................................................................................. 95
Valproic acid ............................................................................................................... 95
Other antiepileptic drugs .............................................................................................. 95
Clonidine ............................................................................................................................ 95
Baclofen ............................................................................................................................. 96
Corticosteroids................................................................................................................... 96
Calcitonin ........................................................................................................................... 97
Bisphosphonates ................................................................................................................ 97
Botulinum toxins ................................................................................................................ 97
Analgesic effect of botulinum toxin A .................................................................................. 98
Engineered botulinum toxin ............................................................................................... 98
Analgesics from traditional medical systems ..................................................................... 98
Herbs and other plants ..................................................................................................... 99
Analgesics derived from cobra toxin ................................................................................. 100
Adverse effects of analgesics ........................................................................................... 100
Gastrointestinal adverse effects of NSAIDs ........................................................................ 100
Measures to reduce gastrointestinal adverse effects of NSAIDs ....................................... 100
Cardiovascular adverse effects of COX-2 inhibitors ............................................................. 100
Adverse effects of opioids ............................................................................................... 101
Risk of addiction and development of tolerance ............................................................. 101
Companies developing products to deter abuse of opioids .............................................. 101
Remoxy versus Oxycontin .......................................................................................... 102
Hyperalgesia associated with opioids ........................................................................... 102
Respiratory depression .............................................................................................. 103
Opioid-associated constipation .................................................................................... 103
Narcotic bowel syndrome ........................................................................................... 103
Adverse effects of use of opioids in non-malignant pain ...................................................... 103
Approaches to reduce adverse effects of opioids ................................................................ 104
PEGylated naloxol ..................................................................................................... 104
Innovative approaches to modify opioid pharmacology .................................................. 104
Regulatory aspects of opioid abuse, overdose and death ................................................ 104
Adverse effects of miscellaneous non-narcotic analgesics .................................................... 105
Adverse effects of immunosuppressants used for relief of pain ........................................ 105
Adverse effects of acetaminophen ............................................................................... 106

4. Management of Pain ........................................................................... 107

Introduction..................................................................................................................... 107
Sites for pain management .............................................................................................. 107
Self-medication at home ................................................................................................. 107
Physicians' offices .......................................................................................................... 107
Major hospitals .............................................................................................................. 107
Pain centers .................................................................................................................. 108
Non-pharmacological approaches to pain ........................................................................ 108
Alternative medicine ....................................................................................................... 108
Acupuncture ............................................................................................................. 109
Aromatherapy........................................................................................................... 109

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Self-Controlled Energo Neuro Adaptive Regulation......................................................... 110

Behavioral therapy ......................................................................................................... 110
Cognition and pain .................................................................................................... 110
Control over brain activation and pain by using functional MRI ........................................ 110
Thermal-grill illusion .................................................................................................. 111
Virtual reality therapy ................................................................................................ 111
Local application of heat ................................................................................................. 111
Transcutaneous nerve stimulation .................................................................................... 112
Transcranial magnetic stimulation .................................................................................... 112
Neurosurgery for pain relief ............................................................................................. 112
Ablative procedures on the nervous system .................................................................. 113
Procedures on peripheral, spinal and cranial nerves ....................................................... 113
Vagal nerve stimulation for control of pain ................................................................... 113
Neuromodulation ...................................................................................................... 113
Spinal cord stimulation .............................................................................................. 114
Brain stimulation ....................................................................................................... 115
Implantation of drug delivery devices .......................................................................... 115
Management of special types of pain ............................................................................... 115
Acute pain..................................................................................................................... 115
Management of acute renal colic: NSAIDS vs. opioids .................................................... 115
Combination of opioids and NSAIDs for acute pain ........................................................ 116
Reasons for inadequate management of acute pain ....................................................... 116
Perioperative pain management ....................................................................................... 116
Devices for delivery of analgesics in the postoperative period ......................................... 117
Drug combination for perioperative pain ...................................................................... 118
Gabapentin for reduction of postoperative pain ............................................................. 118
Ketamine for perioperative pain .................................................................................. 118
Opioids for perioperative pain ..................................................................................... 119
Perioperative pain in neurosurgery .............................................................................. 119
Prolonged duration local anesthesia ............................................................................. 120
Concluding remarks on the management of postoperative pain ....................................... 120
Pain in the intensive care unit .......................................................................................... 121
Pain associated with sports and exercise ........................................................................... 121
Pain associated with trauma ............................................................................................ 122
Chronic abdominal pain .................................................................................................. 122
Functional somatic syndromes ......................................................................................... 122
Fibromyalgia syndrome ................................................................................................... 123
Pathomechanism of FMS ............................................................................................ 123
Management of FMS .................................................................................................. 124
New developments in pharmacotherapy of FMS ............................................................ 124
Erythromelalgia ............................................................................................................. 125
Irritable bowel syndrome ................................................................................................ 126
Opioids for IBS ......................................................................................................... 127
Tricyclic antidepressants for IBS ................................................................................. 127
Serotonin-modulating drugs for IBS ............................................................................ 127
Musculoskeletal pain....................................................................................................... 128
Myofascial pain syndrome ............................................................................................... 128
Osteoarthritis ................................................................................................................ 128
Pathomechanism of osteoarthritis ............................................................................... 128
Pain aggravates osteoarthritis by crosstalk between CNS and the joint ............................ 129
Management of osteoarthritis ..................................................................................... 130
Rheumatoid arthritis ....................................................................................................... 131
Management of pain in rheumatoid arthritis ................................................................. 131
Disease modifying therapies in rheumatoid arthritis....................................................... 131
Resurgence of interest in gold-based treatments for RA ................................................. 132
Backache ...................................................................................................................... 133
Use of analgesics for management of back pain ............................................................ 134
Miscellaneous medical therapies for backache and sciatica ............................................. 134
Neck pain...................................................................................................................... 135
Chronic pelvic pain ......................................................................................................... 135
Prostatitis ................................................................................................................ 136
Cancer pain ................................................................................................................... 136
Opioid treatment of cancer pain .................................................................................. 137
Breakthrough and opioid-insensitive pains.................................................................... 138
Morphine-induced enhancement of cancer growth and its prevention ............................... 138
Methods of delivery of opioids for cancer pain ............................................................... 139
Implantation of drug delivery devices .......................................................................... 139
Management of bone pain in cancer ............................................................................ 140
Use of non-opioid analgesics for cancer pain ................................................................. 140
Adjuvant drugs for cancer pain ................................................................................... 140
Radiation therapy ...................................................................................................... 141

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Alternative non-pharmacological methods .................................................................... 141

Anesthetic techniques ................................................................................................ 141
Surgical methods of cancer pain relief ......................................................................... 141
Conclusions regarding management of cancer pain........................................................ 142
Chronic non-malignant pain............................................................................................. 142
Headache ...................................................................................................................... 143
Migraine................................................................................................................... 143
Management of acute migraine ................................................................................... 143
Neurostimulation for migraine..................................................................................... 147
Transcranial magnetic stimulation for migraine ............................................................. 148
Migraine prophylaxis.................................................................................................. 148
Cluster headache ...................................................................................................... 149
Paroxysmal hemicrania .............................................................................................. 149
Tension headache ..................................................................................................... 149
Chronic daily headache .............................................................................................. 150
Trigeminal neuralgia ....................................................................................................... 150
Dental pain ................................................................................................................... 151
Neuropathic pain............................................................................................................ 151
Pathogenesis of neuropathic pain ................................................................................ 151
Chronobiology of neuropathic pain as guide to therapy .................................................. 152
Management of neuropathic pain based on mechanism .................................................. 153
Guidelines for the management of neuropathic pain ...................................................... 153
Pharmacotherapy of neuropathic pain .......................................................................... 153
Evidence-based management of neuropathic pain ......................................................... 156
Management of central neuropathic pain ........................................................................... 156
Neurosurgical approaches to central neuropathic pain .................................................... 156
Management of neuropathic pain in syringomyelia ........................................................ 157
Neuropathic pain associated with spinal cord injury ....................................................... 157
Peripheral neuropathic pain ............................................................................................. 158
Management of postsurgical peripheral neuropathic pain ................................................ 158
Management of chemotherapy-induced pain ................................................................. 158
Mortons neuroma ..................................................................................................... 159
Management of peripheral diabetic neuropathy ............................................................. 159
Postherpetic neuralgia ............................................................................................... 161
Complex regional pain syndrome ................................................................................ 163
An algorithm for the management of peripheral neuropathic pain .................................... 164
Phantom limb pain ......................................................................................................... 165
Pathomechanism of phantom limb pain ........................................................................ 165
Management of phantom limb pain.............................................................................. 165
Pain and depression ....................................................................................................... 167
Neurochemical link between pain and depression .......................................................... 168
Management of chronic pain and depression ................................................................. 168
Miscellaneous painful conditions ....................................................................................... 169
Burning mouth syndrome ........................................................................................... 169
Chronic unstable angina ............................................................................................. 170
Mastalgia ................................................................................................................. 170
Ophthalmic pain ........................................................................................................ 170
Pain in Parkinson's disease ......................................................................................... 171
Management of chronic unexplained pain .......................................................................... 171
Management of itching ................................................................................................... 172
Topical applications for itching .................................................................................... 172
Systemic therapies for itching ..................................................................................... 173
Non-pharmacological therapies for itch ........................................................................ 174
Management of pain in special population groups ........................................................... 174
Racial and ethnic differences in pain management ............................................................. 174
Pain in neonates ............................................................................................................ 174
Management of pain in children ....................................................................................... 175
Management of pain in the elderly ................................................................................... 176
Management of pain in women ........................................................................................ 177
Reasons for increased pain perception in women........................................................... 177
Chronic pelvic pain in women ..................................................................................... 177
Gender differences in response to analgesics ................................................................ 178
Considerations for pain management in women ............................................................ 178
Management of pain in neurologically handicapped persons ................................................ 178
Management of pain in the cognitively impaired elderly people ............................................ 179
Management of pain in brain-damaged minimally conscious patients .................................... 179
Management of pain in the terminally ill............................................................................ 180
Problems in the management of pain............................................................................... 180
Inadequate pain management ......................................................................................... 180
Regulation of use of opioids ............................................................................................. 181
Suggestions for improvement of pain management by healthcare providers .......................... 181

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Pain as the fifth vital sign ................................................................................................ 183

Management of neuropathic pain in patients refractory to first line treatment ........................ 183
Multidisciplinary approaches to pain management .......................................................... 183

5. Drug Delivery for Pain ........................................................................ 185

Introduction..................................................................................................................... 185
Intra-articular injection for relief of joint pain ................................................................. 186
Delivery of analgesics to peripheral nerves ..................................................................... 186
Controlled release drug delivery for pain ......................................................................... 186
Accelerating the effect of subcutaneous morphine .............................................................. 186
Controlled drug delivery at site of pain ............................................................................. 187
Oral extended release opioids .......................................................................................... 187
Extended release oral morphine .................................................................................. 187
Controlled release oxycodone ..................................................................................... 188
Extended release oxymorphone .................................................................................. 188
Oral extended release tramadol .................................................................................. 188
Extended release gabapentin ........................................................................................... 189
Use of nanotechnology for drug delivery for pain................................................................ 189
Non-injection methods of delivery of analgesics .............................................................. 189
Topical applications for pain ............................................................................................ 190
Topical local anesthetics............................................................................................. 190
Topical NSAIDs ......................................................................................................... 191
Topical and transdermal diclofenac .............................................................................. 191
Topical application for postoperative pain ..................................................................... 192
Needle-free drug delivery for pain .................................................................................... 192
Glide SDI solid dose injector .................................................................................... 192
SUMAVEL DosePro needle-less injection.................................................................. 192
Transdermal drug delivery for pain ................................................................................... 193
Relief of pain associated with minor medical procedures ................................................ 193
Transdermal fentanyl ................................................................................................. 193
Transdermal ketoprofen ............................................................................................. 194
Transdermal nitroglycerine as an adjuvant to opioids..................................................... 195
Transdermal buprenorphine........................................................................................ 195
Transdermal trans-capsaicin ....................................................................................... 196
Powder Injection Systems .......................................................................................... 196
Intranasal delivery of analgesics ...................................................................................... 197
Intranasal morphine .................................................................................................. 197
Intranasal morphine derivatives .................................................................................. 197
Intranasal fentanyl .................................................................................................... 198
Intranasal buprenorphine ........................................................................................... 198
Intranasal ketamine .................................................................................................. 199
Intranasal ketorolac .................................................................................................. 199
Nasal formulations for migraine .................................................................................. 199
Oral spray formulations for migraine ................................................................................ 200
Delivery of analgesics by inhalation .................................................................................. 200
Buccal transmucosal and sublingual delivery of analgesics .................................................. 201
Application for cancer pain ......................................................................................... 201
Application for non-cancer pain ................................................................................... 201
Pumps for drug delivery in pain ....................................................................................... 202
Patient controlled analgesia ........................................................................................ 202
Postoperative pain pumps .......................................................................................... 202
Chronogesic (sufentanil) Pain Therapy System .............................................................. 203
Spinal pumps for delivery of analgesics ........................................................................ 204
Spinal delivery of analgesics ............................................................................................ 204
Epidural administration of analgesics ................................................................................ 206
Epidural dexamethasone ............................................................................................ 206
Epidural etanercept ................................................................................................... 206
Epidural morphine ..................................................................................................... 206
Intrathecal administration of analgesics ............................................................................ 206
Intrathecal CGX1160 ................................................................................................. 206
Intrathecal fadolmidine .............................................................................................. 206
Intrathecal lidocaine .................................................................................................. 207
Intrathecal neostigmine ............................................................................................. 207
Intrathecal non-NMDA antagonists .............................................................................. 207
Intrathecal prostaglandin antagonists .......................................................................... 207
Intrathecal resiniferatoxin .......................................................................................... 208
Intrathecal ziconotide ................................................................................................ 208
Concluding remarks on intrathecal delivery of analgesic agents ...................................... 209
Intracerebroventricular morphine for pain ...................................................................... 209
Development of drug delivery systems for pain therapy .................................................. 209
Delivery of analgesics to the CNS across the blood brain barrier .......................................... 210

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Drug delivery systems in clinical trials .............................................................................. 210

6. Drug Development for Pain ................................................................. 213

Introduction..................................................................................................................... 213
Drugs in development for pain ......................................................................................... 213
Current research goals ..................................................................................................... 214
The ideal analgesic ......................................................................................................... 214
Pain R & D goals in the pharmaceutical industry................................................................. 214
Drug targets in the spinal cord ........................................................................................ 215
Drug targets in the brain ................................................................................................. 215
Molecular targets for analgesic drugs .............................................................................. 215
Activation of P2X7 receptors ............................................................................................ 215
Adenosine receptor agonists ............................................................................................ 216
Alfa2-adrenergic receptor agonists ................................................................................... 216
Anti-NGF strategies ........................................................................................................ 216
Bradykinin antagonists ................................................................................................... 217
Cannabinoids ................................................................................................................. 217
Cannabinoid receptor agonists .................................................................................... 218
Cannabidiol .............................................................................................................. 219
Cannabinor .............................................................................................................. 220
Nabilone .................................................................................................................. 220
Capsaicin and VR1 receptor-based analgesics .................................................................... 221
Vanilloid (capsaicin) receptor antagonists ..................................................................... 221
VR1 receptor agonists ................................................................................................ 221
CCR2 receptor blockade .................................................................................................. 222
Cholecystokinin antagonists ............................................................................................ 222
Cholinergic receptor agonists ........................................................................................... 222
Conotoxins as analgesics ................................................................................................ 223
Corticotropin-releasing factor .......................................................................................... 224
FAAH inhibitors .............................................................................................................. 224
PF-3845 ................................................................................................................... 225
URB597 ................................................................................................................... 225
Free radical scavengers as analgesics ............................................................................... 225
Superoxide dismutase mimetics .................................................................................. 226
GABA analogues ............................................................................................................ 226
Subtype-selective GABAergic drugs ............................................................................. 226
Glial cell line-derived neurotrophic factor .......................................................................... 227
Glutamate receptor antagonists ....................................................................................... 227
NMDA receptor modulation for neuropathic pain............................................................ 227
Alternatives to direct blocking of NMDA receptors.......................................................... 228
Glycine antagonists ................................................................................................... 228
Metabotropic glutamate receptors ............................................................................... 228
Histogranin-like compounds for the management of pain .................................................... 229
Ion channels as targets for analgesic drugs ....................................................................... 229
Acid-sensing ion channels as drug target ..................................................................... 229
Calcium channel blockers ........................................................................................... 230
P2X ion channel receptor antagonists .......................................................................... 230
Sodium channel modulation ....................................................................................... 231
Mas-related GPCR agonists.............................................................................................. 231
Microsomal prostaglandin E synthase inhibitors.................................................................. 232
NAALADase inhibitors ..................................................................................................... 233
Nerve growth factor antagonists ...................................................................................... 233
Newer COX inhibitors...................................................................................................... 233
COX-3 inhibitors ....................................................................................................... 234
Dual cyclooxygenase/lipoxygenase inhibitors ................................................................ 234
Neuropeptide receptor antagonists for improving the efficacy of opioids ................................ 234
Nicotinic acetylcholine receptors ...................................................................................... 234
Mode of action of nACh/neural nicotinic receptor agonists .............................................. 235
Potential of central nACh/neural nicotinic receptor agonists ............................................ 235
Nitric oxide-based analgesics ........................................................................................... 236
Nitric oxide-releasing NSAIDs ..................................................................................... 236
Pharmacology of NO-SAIDs ........................................................................................ 237
COX-inhibiting nitric oxide donors ............................................................................... 237
NO-donating structures to extend life cycle of existing analgesics.................................... 238
Nitric oxide mimetics ................................................................................................. 238
Neuronal nitric oxide synthase inhibitors ...................................................................... 238
Norepinephrine transporter inhibition ............................................................................... 238
Opioid peptide receptors ligands ...................................................................................... 239
Opioids with unique receptor characteristics ................................................................. 240
Buprenorphine .......................................................................................................... 240
Nociceptin ................................................................................................................ 240

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Tapentadol ............................................................................................................... 241

Opioid analgesics acting outside the CNS .......................................................................... 241
Opioid analgesics acting at peripheral receptors ............................................................ 241
Peripherally acting mu-opioid receptor agonists ............................................................ 242
Targeting of opioid peptide-containing immune cells ...................................................... 242
Advantages of peripherally selective opioid drugs .......................................................... 242
Resolvins ...................................................................................................................... 243
Somatostatin analogs ..................................................................................................... 243
Substance P and neurokinin receptor antagonists ............................................................... 243
Substance P-Saporin ...................................................................................................... 244
Targeting prostanoid synthesis ........................................................................................ 244
Tetrodotoxin based analgesics ......................................................................................... 245
TRPV1 antagonists ......................................................................................................... 245
TRPV1 antagonists in clinical trials............................................................................... 246
TRPV1-mediated entry of sodium channel blocker QX-314 .............................................. 247
Tumor necrosis factor- antagonists ................................................................................. 247
Biological therapies for pain ............................................................................................ 247
Cell therapy for pain ........................................................................................................ 248
Cells for delivery of antinociceptive molecules.................................................................... 249
Cell therapy for low back pain.......................................................................................... 249
Cell therapy for knee pain due to degenerative disorders .................................................... 249
Cell therapy for peripheral neuropathic pain ...................................................................... 250
Cell transplantation for relief of pain ................................................................................. 250
Transplantation of chromaffin cells .............................................................................. 250
Transplantation of stem cells ...................................................................................... 251
Transplantation of astrocytes secreting enkephalin ........................................................ 251
Transplantation of cells for relief of neuropathic pain ..................................................... 251
Concluding remarks on cell therapy for pain ...................................................................... 252
Gene therapy for pain ...................................................................................................... 252
Rationale of gene therapy for pain ................................................................................... 253
Gene therapy of peripheral neuropathy ........................................................................ 253
Gene therapy targeted to neuroimmune component of chronic pain................................. 254
Methods of gene delivery for pain .................................................................................... 254
Vectors for gene therapy of pain ...................................................................................... 255
Vectors for endogenous analgesic production in cranial neuralgias................................... 255
Methods of gene delivery for pain .................................................................................... 255
Gene delivery by intrathecal route ............................................................................... 255
Gene transfer to the dorsal nerve roots........................................................................ 256
Gene transfer by injections into the brain substance ...................................................... 257
Antisense therapy for pain .............................................................................................. 257
RNAi-based approaches for pain therapy ........................................................................... 258
Potential applications of gene therapy for management of pain ............................................ 259
Gene therapy for producing enkephalin to block pain signals .......................................... 259
Gene therapy for upregulation of BMP in backache ........................................................ 260
Gene therapy for targeting nuclear factor-B ................................................................ 260
Gene therapy for neuropathic pain .............................................................................. 260
Zinc finger DNA-binding protein therapeutic for chronic pain........................................... 261
Concluding remarks about gene therapy for pain ............................................................... 261
Preclinical development of pain drugs ............................................................................. 262
NGF-blocking antibody .................................................................................................... 263
Prostatic acid phosphatase as a novel analgesic ................................................................. 263
Preclinical development of drugs for neuropathic pain ......................................................... 263
5-HT receptor agonists .............................................................................................. 264
A-803467 ................................................................................................................. 265
AM1241 ................................................................................................................... 265
Artemin/Neuroblastin ................................................................................................ 265
Capsazepine ............................................................................................................. 266
Central nACh receptor agonists ................................................................................... 266
CGP 35024 ............................................................................................................... 266
Drugs that suppress glial activation ............................................................................. 267
Erythropoietin ........................................................................................................... 267
NCX 8001 ................................................................................................................ 267
NR2B subtype NMDA receptor ligands .......................................................................... 268
NW-1029 ................................................................................................................. 268
R116301 .................................................................................................................. 269
Targeting tumor necrosis factor .................................................................................. 269
Future targets for osteoarthritic pain ................................................................................ 269
Pain drugs in clinical trials ............................................................................................... 269
Clinical trials of miscellaneous drugs for pain ..................................................................... 270
Alvimopan ................................................................................................................ 271
Asimadoline.............................................................................................................. 272

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EN3202 ................................................................................................................... 272

Oxytrex ................................................................................................................... 272
Drugs in clinical trials for postsurgical pain ........................................................................ 273
Bicifadine ................................................................................................................. 274
DepoMorphine .......................................................................................................... 274
Cox-2 inhibitors in clinical trials ....................................................................................... 275
Clinical trials of disease modifying therapies for arthritis ..................................................... 275
Drugs in clinical development for neuropathic pain ............................................................. 277
Adenosine A1 agonists for neuropathic pain .................................................................. 279
AVP-923 (dextromethorphan + quinidine) .................................................................... 280
Botulinum toxin type A .............................................................................................. 280
CNV1014802 ............................................................................................................ 280
CPL7075 .................................................................................................................. 280
D-amino acid oxidase inhibitors .................................................................................. 281
Glyx-13 ................................................................................................................... 281
IP-751 ..................................................................................................................... 281
Lacosamide .............................................................................................................. 282
Oxcarbazepine .......................................................................................................... 282
Perampanel .............................................................................................................. 282
Ralfinamide .............................................................................................................. 283
Retigabine ................................................................................................................ 283
SB-509 .................................................................................................................... 283
SCP-1 ...................................................................................................................... 283
TC-6499 .................................................................................................................. 284
Tebanicline ............................................................................................................... 284
Tezampanel .............................................................................................................. 284
Thalidomide ............................................................................................................. 285
TRO19622 ................................................................................................................ 285
V3381 (indantadol) ................................................................................................... 285
XP-13512 ................................................................................................................. 286
Zonisamide .............................................................................................................. 286
Drug discovery and development for migraine ................................................................... 286
Drugs in clinical development for migraine ................................................................... 287
Clinical development of preventive therapies for migraine .............................................. 289
Drug development for visceral pain .................................................................................. 289

7. Legal and regulatory issues of pain management ............................... 291

Pain relief as a legal right ................................................................................................ 291
Pain relief and the WHO ................................................................................................... 291
Regulatory issues ............................................................................................................ 291
Opioids and cannabinoids ................................................................................................ 291
DEA and use of opioids for pain relief in terminal care ........................................................ 291
FDA and COX-2 inhibitors................................................................................................ 292
Legal issues of COX-2 inhibitors....................................................................................... 293
Regulatory issues of opioid safety ................................................................................... 293
Opioid misuse and regulatory agencies ............................................................................. 293
FDA measures for safety of opioid use .............................................................................. 293
Misuse of fentanyl .......................................................................................................... 294

8. Pain Markets ....................................................................................... 295

Introduction..................................................................................................................... 295
Epidemiological basis of pain markets ............................................................................. 295
Cancer .......................................................................................................................... 296
Neuropathic pain............................................................................................................ 296
Trigeminal neuralgia ....................................................................................................... 296
Arthritis ........................................................................................................................ 296
Backache ...................................................................................................................... 296
Migraine ....................................................................................................................... 297
Multiple sclerosis ............................................................................................................ 297
Irritable bowel syndrome ................................................................................................ 297
Chronic pelvic pain ......................................................................................................... 297
Chronic pain due to traumatic brain injury......................................................................... 297
Postsurgical pain ............................................................................................................ 298
Economics of pain ............................................................................................................ 298
Pain as a driver of healthcare costs .................................................................................. 298
Disability and financial loss through pain ........................................................................... 299
Pain markets based on painful conditions ........................................................................ 299
The cancer pain market .................................................................................................. 299
The arthritis pain market ................................................................................................ 300
Postsurgical pain market ................................................................................................. 300
The backache market ..................................................................................................... 300

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The headache market ..................................................................................................... 301

Neuropathic pain market ................................................................................................. 301
Fibromyalgia market ...................................................................................................... 302
Pain markets based on drugs ........................................................................................... 302
Opioids ......................................................................................................................... 302
Nonsteroidal antiinflammatory drugs ................................................................................ 303
Transdermal pain therapeutics ......................................................................................... 303
Anesthesia .................................................................................................................... 303
Antiepileptic drugs as analgesics ...................................................................................... 304
Other drugs ................................................................................................................... 304
Hospital vs retail share of pain market .............................................................................. 304
Hospital versus retail opioid market ............................................................................. 304
Devices for pain ............................................................................................................. 304
Pain markets according to geographical areas ................................................................. 305
Cost effectiveness of various approaches ........................................................................ 305
Unfulfilled R&D needs in pain therapy ............................................................................. 306
Under treatment of pain.................................................................................................. 306
Unfulfilled needs in drug development for chronic pain ....................................................... 306
Strategies for developing pain markets ........................................................................... 307
Finding alternatives to intrathecal administration for chronic pain ........................................ 307
Development of other applications of analgesic drugs ......................................................... 307
Partnership of patients, pharmacists and companies ........................................................... 308
Factors that may influence future pain markets............................................................... 308
Drivers of pain markets .................................................................................................. 308
Public surveys as indicators of impact of pain on people ...................................................... 309
Effect of regulatory reviews on markets for pain products ................................................... 309
Novel versus older therapies for pain ................................................................................ 310

9. Future of Pain Therapeutics ................................................................ 311

Introduction..................................................................................................................... 311
Advances in the understanding of pain ............................................................................ 311
Pathogenesis of chronic pain ........................................................................................... 311
Role of glia in neuropathic pain ........................................................................................ 311
Molecular and neurobiological techniques .......................................................................... 312
Improved understanding of cancer pain ............................................................................ 313
Advances in drug discovery and development for pain .................................................... 313
Novel targets for drug discovery for pain........................................................................... 313
PTH2 receptor........................................................................................................... 313
Modulators of endogenous cannabinoids ...................................................................... 314
Application of new technologies to pain therapeutics .......................................................... 314
Application of nanobiotechnology to pain therapeutics ................................................... 315
Technologies for the manufacture of analgesics ............................................................ 316
Future trends and needs in pain management ................................................................. 316
Pain management in future healthcare systems .............................................................. 317
Systems biology approach to pain ................................................................................... 317
Personalized pain management ....................................................................................... 318
Pharmacogenomics and pharmacogenetics of pain ............................................................. 319
Genetic mutations associated with reduced response to analgesics ....................................... 320
Genetic mutations with loss of pain .................................................................................. 320
Mechanism-specific management of pain .......................................................................... 321
Preoperative testing to tailor postoperative analgesic requirements ...................................... 321
Strategies for improving pain management ..................................................................... 321

10.

Companies Involved in Pain Therapeutics................................... 323

Introduction..................................................................................................................... 323
Profiles of companies ....................................................................................................... 323
Collaborations .................................................................................................................. 492

11.

References .................................................................................. 497

Tables

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Landmarks in the history of pain therapeutics ................................................................ 20

Classification of pain ................................................................................................... 22
Classification of neuropathic pain ................................................................................. 24
Classification of chronic cancer pain according to cause ................................................... 26
Percentage of patients with pain according to the type of cancer ...................................... 27
Key molecular elements of pain in the peripheral nervous system .................................... 49
Key molecular elements of pain in the central nervous system ......................................... 49

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2-1: IASP guidelines for the use of animals in pain studies ..................................................... 62
2-2: Chronic pain as a manifestation of other diseases ........................................................... 63
2-3: Recommendations for assessing patient satisfaction with pain management ...................... 68
3-1: Classification of some currently used pain medications according to mechanism ................. 75
3-2: Drugs used for the treatment of pain ............................................................................ 75
3-3: Selective COX-2 inhibitors in clinical use for pain ............................................................ 77
3-4: Antiepileptic drugs with analgesic effect ........................................................................ 91
3-5: Companies with products to deter abuse of opioids ....................................................... 102
4-1: Non-pharmacological approaches to management of pain.............................................. 108
4-2: Companies involved in neuromodulation therapy for pain .............................................. 114
4-3: Reasons for the inadequate management of acute pain ................................................. 116
4-4: Causes of chronic backache ....................................................................................... 133
4-5: Management of chronic pelvic pain ............................................................................. 135
4-6: Management of pain in cancer ................................................................................... 136
4-7: Definitions of tolerance, physiological dependence, withdrawal and addiction ................... 142
4-8: A simplified classification of headache ......................................................................... 143
4-9: Various methods for the management of migraine ........................................................ 144
4-10: Management of neuropathic pain based on mechanism and diagnosis ........................... 153
4-11: Management of central neuropathic pain ................................................................... 156
4-12: Current management of peripheral diabetic neuropathy .............................................. 159
4-13: Treatment strategies for postherpetic neuralgia .......................................................... 161
4-14: Management of complex regional pain syndrome ........................................................ 163
4-15: Methods of treating phantom limb pain ..................................................................... 165
4-16: Treatment of chronic unexplained pain due to central sensitization ............................... 171
4-17: Anti-itching therapies .............................................................................................. 172
4-18: Suggested improvements in the management of pain ................................................. 182
5-1: A classification of drug delivery methods used in management of pain ............................ 185
5-2: Selected marketed non-injection drug delivery systems for pain..................................... 190
5-3: Spinal administration of drugs for pain ........................................................................ 204
5-4: Selected drug delivery systems for pain in clinical development ..................................... 210
6-1: Classification of drugs in development for pain ............................................................. 213
6-2: Preclinical studies on cannabinoid (CB2) receptor agonists as analgesics ......................... 218
6-3: Cannabinoid receptor agonists in clinical development as analgesics ............................... 219
6-4: NO-related therapies for pain ..................................................................................... 236
6-5: Major opioids receptors and their ligands..................................................................... 239
6-6: Strategies to counteract pain at various levels at periphery and in the CNS ..................... 245
6-7: Types of TRPV1 antagonists ....................................................................................... 246
6-8: TRPV1 antagonists in clinical trials .............................................................................. 246
6-9: Experimental gene therapy approaches for relief of pain ............................................... 254
6-10: Selected preclinical approaches to pain therapy .......................................................... 262
6-11: Selected preclinical drugs for neuropathic pain ........................................................... 263
6-12: Selected clinical trials of miscellaneous drugs for pain ................................................. 270
6-13: Selected clinical trials of drugs for postsurgical pain .................................................... 273
6-14: COX-2 inhibitors in clinical development .................................................................... 275
6-15: Disease modifying drugs for arthritis in clinical trials ................................................... 275
6-16: Clinical trials of drugs for neuropathic pain ................................................................ 277
6-17: Selected drugs in clinical development for migraine .................................................... 287
6-18: Therapeutic targets for treating visceral pain ............................................................. 290
8-1: Market values for various painful conditions 2011-2021 ................................................ 299
8-2: Changes in market shares of drugs for neuropathic pain 2011-2021 ............................... 301
8-3: Markets for pain according to therapies 2011-2021 ...................................................... 302
8-4: Distribution of value of pain therapeutics in major markets 2011-2021 ........................... 305
8-5: Distribution of value of opioids in major pain markets 2011-2021 ................................... 305
8-6: Distribution of value of NSAIDs in major pain markets 2011-2021 .................................. 305
8-7: Strategies for developing pain markets ....................................................................... 307
9-1: P450 isoforms in the metabolism of drugs used in the management of pain ..................... 319
10-1: Product pipeline of Adolor Corporation....................................................................... 329
10-2: Selected collaborations in the area of pain management .............................................. 492

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Afferent pain pathways .............................................................................................. 29

Evolution of the gate control theory ............................................................................. 31
The body self-neurometric.......................................................................................... 31
Various ligands and receptors on the peripheral terminals of nociceptive nerve fibers ........ 49
Prostaglandin biosynthesis pathway............................................................................. 53
Biopsychosocial factors that interact and modulate the experience of pain........................ 64
Pain intensity scales .................................................................................................. 65
The WHO step ladder for pain ................................................................................... 137
An algorithm for the acute management of migraine ................................................... 145

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Neuroimmune activation events leading to sensitization of CNS .................................... 152

An algorithm for the management of peripheral neuropathic pain .................................. 164
Algorithm for management of patients with chronic pain and depression ........................ 169
Powder Injection Systems ........................................................................................ 196
Attributes of the ideal analgesic ................................................................................ 214
Nerve targeting drug delivery system for gene therapy of pain ..................................... 259
Unfulfilled needs in the treatment for chronic pain ....................................................... 306
Impact of new technologies on pain therapeutics ........................................................ 315
A scheme of personalized management of pain ........................................................... 318

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