Pain Therapeutics - Drugs, Markets and Companies

Table of Contents

0. Executive Summary 19

1. Basic Aspects of Pain 21

• Introduction 21
• Historical aspects of pain 21
• Pain definitions 23
• A glossary of terms relevant to pain 24
• Pain classification and description 24
• Neuropathic pain 25
• Cancer pain 27
• Bone pain in cancer 29
• Complex regional pain syndrome 29
• Mechanisms of pain 30
• Pain pathways 30
• Role of nociceptors in pain transmission 31
• Gate control and neuromatrix theories of pain 32
• Pain mediators 33
• Role of the sympathetic nervous system in pain 33
• Visceral pain 34
• Pathomechanism of visceral pain 34
• Pathomechanism of neuropathic pain 34
• Role of intact nerve fibers in neuropathic pain 34
• Chemokines as mediators of neuropathic pain 35
• Chemotherapy-induced neuropathic pain 35
• CNS innate immunity and neuropathic pain 35
• Cytokines as mediators of neuropathic pain 36
• Free radicals in generation of neuropathic pain 36
• Genetic basis of neuropathic pain 36
• Gene expression changes in neuropathic pain 36
• Glial activation and neuropathic pain 37
• Immune cell-derived opioids and neuropathic pain 37
• Spinal leptin and neuropathic pain 38
• Tetrahydrobiopterin regulates of neuropathic pain sensitivity 38
• Pathomechanism of migraine 38
• Role of the immune system in pain 39
• Pain and itch 39
• Pathomechanism of itch 40
• Clinical aspects of itch 40
• Molecular pathophysiology of pain 40
• Role of ion channels in pain 41
• Role of sodium channels in pain 41
• Role of potassium ion channels 42
• Role of calcium channels in pain 42
• Acid-sensing ion channels 43
• P2X3 ion channels 44
• Role of TRP ion channels in pain 44
• Genetic basis of pain 45
• Study of genes in pain 45
• Pain in the brain 46
• Neuropathic pain-induced morphological changes in the brain 46
• Change from acute to chronic pain 46
• Role of neuronal plasticity in pain 47
• Descending facilitatory modulation of pain 47
• Pain and transcriptional repressor DREAM 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 49
• Role of AMPA receptors in chronic pain 50
• Kinins 50
• Serotonin 50
• Substance P 51
• Excitatory amino acids 51
• Role of nitric oxide in pain 51
• Prostaglandins 52
• Endocannabinoids 53
• Protein kinase C 53
• Adenosine and adenosine receptors 53
• Vitamin D and pain 53
• Vanilloid receptor 54
• TRPA1 and TRPV1 receptors 54
• Endothelin-B receptors 55
• Nerve growth factor and pain 55
• Adrenomedullin as a pain-related peptide 55
• Biomarkers of pain 56
• Biomarkers of visceral pain 56

2. Assessment of Pain and Analgesics 57

• Introduction 57
• Animal models of pain 57
• An overview 57
• Selection of animal species as models for pain 57
• Types of noxious stimuli 57
• Animal models of neuropathic pain 58
• Animal models of arthritis 58
• Animal models of peripheral neuropathy 59
• Limitations of current pain models 59
• Biogenic Animal Model of Chronic Pain 60
• Ethical issues concerning animal pain models 60
• Medical evaluation of pain 61
• Chronic pain as a manifestation of various diseases 61
• Assessment of pain patients 61
• Medical examination 61
• Measurement of pain 62
• Quantitative sensory testing 63
• Pain measurement tools for neonates and children 64
• Quantitative sensory testing 64
• Psychological assessment of pain 65
• Brain imaging in pain 65
• Patient outcomes and quality of life during treatment for chronic pain 66
• Collection and analysis of data on pain patients 66
• Evaluation of analgesics 67
• Study of pain in humans 67
• Testing of analgesics in humans 67
• Design of clinical trials for pain 68
• Assessment of neuropathic pain 69
• Placebo effect in pain 69
• Role of electronic pain recording in determination of the placebo effect 70
• Outcome measures for chronic pain trials 70
• Pain, pain therapies and cognitive function 71

3. Pharmacotherapy of Pain 73

• Introduction 73
• Mechanism of action of currently used pain medications 73
• Non-steroidal antiinflammatory drugs 74
• COX-2 inhibitors 74
• Celecoxib 75
• Nimesulide 76
• Rofecoxib 76
• Valdecoxib 77
• Lumiracoxib 77
• Side effects of COX inhibitors 77
• Safety aspects of COX-2 inhibitors in development 79
• Acetaminophen 80
• Antioxidants as analgesics 80
• Opiates and opioids 80
• Innovations in opioid therapy 81
• Oral transmucosal fentanyl 81
• Use of opioids for chronic non-cancer pain 82
• Opioid receptor modulation for visceral pain 82
• Opiorphin 82
• N-methyl-D-aspartate receptor antagonists 83
• Ketamine 83
• CNS 5161 83
• Triptans for treatment of non-migrainous pain 83
• Capsaicin 84
• NGX-4010 84
• Local anesthetics 85
• Topical application 85
• Nerve blocks 85
• Injection of local anesthetics for analgesia 85
• Ultrasound-guided nerve blocks 85
• Topical salicylates for the treatment of pain 86
• Topical rubefacients for acute and chronic pain in adults 86
• Adjunctive analgesics 86
• Antidepressants 86
• Mechanism of analgesic action of antidepressants 87
• Antiepileptic drugs 88
• Mechanism of action of antiepileptic drugs in neuropathic pain 89
• Carbamazepine 89
• Gabapentin 90
• Lamotrigine 90
• Phenytoin 91
• Pregabalin 91
• Topiramate 92
• Valproic acid 92
• Other antiepileptic drugs 92
• Clonidine 93
• Baclofen 93
• Corticosteroids 93
• Calcitonin 94
• Bisphosphonates 94
• Botulinum toxins 94
• Analgesic effect of botulinum toxin A 95
• Engineered botulinum toxin 95
• Adverse effects of analgesics 96
• Gastrointestinal adverse effects of NSAIDs 96
• Measures to reduce gastrointestinal adverse effects of NSAIDs 96
• Cardiovascular adverse effects of COX-2 inhibitors 96
• Adverse effects of opioids 97
• Risk of addiction and development of tolerance 97
• Companies developing products to deter abuse of opioids 97
• Remoxy versus Oxycontin 98
• Hyperalgesia associated with opioids 98
• Respiratory depression 99
• Opioid-associated constipation 99
• Approaches to reduce adverse effects of opioids 99
• PEGylated naloxol 99
• Innovative approaches to modify opioid pharmacology 99
• Adverse effects of non-narcotic analgesics 100
• Adverse effects of immunosuppressants used for relief of pain 100

4. Management of Pain 101

• Introduction 101
• Sites for pain management 101
• Self-medication at home 101
• Physicians' offices 101
• Major hospitals 101
• Pain centers 102
• Non-pharmacological approaches to pain 102
• Alternative medicine 102
• Acupuncture 103
• Herbs and other plants 103
• Aromatherapy 104
• Self-Controlled Energo Neuro Adaptive Regulation 104
• Behavioral therapy 105
• Cognition and pain 105
• Control over brain activation and pain by using functional MRI 105
• Virtual reality therapy 105
• Local application of heat 106
• Transcutaneous nerve stimulation 106
• Transcranial magnetic stimulation 106
• Neurosurgery for pain relief 107
• Ablative procedures on the nervous system 107
• Procedures on peripheral, spinal and cranial nerves 107
• Vagal nerve stimulation for control of pain 108
• Neuromodulation 108
• Spinal cord stimulation 108
• Brain stimulation 109
• Implantation of drug delivery devices 109
• Management of special types of pain 109
• Acute pain 109
• Management of acute renal colic: NSAIDS vs. opioids 110
• Combination of opioids and NSAIDs 110
• Reasons for inadequate management of acute pain 110
• Perioperative pain management 110
• Opioids for perioperative pain 111
• Gabapentin for reduction of postoperative pain 111
• Ketamine for perioperative pain 112
• Drug combination for perioperative pain 112
• Prolonged duration local anesthesia 112
• Perioperative pain in neurosurgery 112
• Devices for delivery of analgesics in the postoperative period 113
• Pain in the intensive care unit 114
• Pain associated with sports and exercise 115
• Chronic abdominal pain 115
• Functional somatic syndromes 115
• Fibromyalgia syndrome 116
• Pathomechanism of FMS 116
• Management of FMS 117
• New developments in pharmacotherapy of FMS 117
• Erythromelalgia 118
• Irritable bowel syndrome 118
• Opioids for IBS 119
• Tricyclic antidepressants for IBS 119
• Serotonin-modulating drugs for IBS 120
• Musculoskeletal pain 120
• Myofascial pain syndrome 120
• Osteoarthritis 121
• Pathomechanism of osteoarthritis 121
• Pain aggravates osteoarthritis by crosstalk between CNS and the joint 122
• Management of osteoarthritis 122
• Rheumatoid arthritis 123
• Management of pain in rheumatoid arthritis 124
• Disease modifying therapies in rheumatoid arthritis 124
• Resurgence of interest in gold-based treatments for RA 125
• Backache 125
• Use of analgesics for management of back pain 126
• Miscellaneous medical therapies for backache and sciatica 127
• Neck pain 127
• Chronic pelvic pain 128
• Prostatitis 128
• Cancer pain 128
• Opioid treatment of cancer pain 129
• Breakthrough and opioid-insensitive pains 131
• Methods of delivery of opioids for cancer pain 131
• Implantation of drug delivery devices 132
• Management of bone pain in cancer 132
• Use of non-opioid analgesics for cancer pain 132
• Adjuvant drugs for cancer pain 133
• Radiation therapy 133
• Alternative non-pharmacological methods 133
• Anesthetic techniques 133
• Surgical methods of cancer pain relief 133
• Conclusions regarding management of cancer pain 134
• Chronic non-malignant pain 134
• Headache 135
• Migraine 135
• Management of acute migraine 135
• Neurostimulation for migraine 139
• Transcranial magnetic stimulation for migraine 140
• Migraine prophylaxis 141
• Cluster headache 141
• Tension headache 141
• Chronic daily headache 142
• Trigeminal neuralgia 142
• Dental pain 143
• Neuropathic pain 143
• Pathogenesis of neuropathic pain 143
• Chronobiology of neuropathic pain as guide to therapy 144
• Management of neuropathic pain based on mechanism 144
• Guidelines for the management of neuropathic pain 145
• Pharmacotherapy of neuropathic pain 145
• Evidence-based management of neuropathic pain 147
• Management of central neuropathic pain 148
• Neurosurgical approaches to central neuropathic pain 148
• Management of neuropathic pain in syringomyelia 148
• Neuropathic pain associated with spinal cord injury 149
• Peripheral neuropathic pain 149
• Management of postsurgical peripheral neuropathic pain 150
• Management of chemotherapy-induced pain 150
• Morton' s neuroma 150
• Management of peripheral diabetic neuropathy 151
• Postherpetic neuralgia 152
• Complex regional pain syndrome 154
• An algorithm for the management of peripheral neuropathic pain 156
• Phantom limb pain 156
• Pathomechanism of phantom limb pain 156
• Management of phantom limb pain 157
• Pain and depression 159
• Neurochemical link between pain and depression 160
• Management of chronic pain and depression 160
• Miscellaneous painful conditions 161
• Burning mouth syndrome 161
• Chronic unstable angina 161
• Mastalgia 162
• Ophthalmic pain 162
• Pain in Parkinson' s disease 162
• Management of itching 162
• Topical applications for itching 163
• Systemic therapies for itching 164
• Non-pharmacological therapies for itch 165
• Management of pain in special population groups 165
• Racial and ethnic differences in pain management 165
• Pain in neonates 165
• Management of pain in children 166
• Management of pain in the elderly 166
• Management of pain in women 167
• Reasons for increased pain perception in women 168
• Chronic pelvic pain in women 168
• Gender differences in response to analgesics 168
• Considerations for pain management in women 169
• Management of pain in neurologically handicapped persons 169
• Management of pain in the cognitively impaired elderly people 169
• Management of pain in brain-damaged minimally conscious patients 170
• Management of pain in the terminally ill 170
• Deficiencies in the management of pain 171
• Negative physician attitudes in pain management 171
• Suggestions for improvement of pain management by healthcare providers 172
• Pain as the fifth vital sign 173
• Multidisciplinary approaches to pain management 173

5. Drug Delivery for Pain 175

• Introduction 175
• Intra-articular injection for relief of joint pain 176
• Controlled release drug delivery for pain 176
• Accelerating the effect of subcutaneous morphine 176
• Controlled drug delivery at site of pain 176
• Oral extended release opioids 177
• Extended release oral morphine 177
• Controlled release oxycodone 177
• Extended release oxymorphone 178
• Oral extended release tramadol 178
• Extended release gabapentin 179
• Use of nanotechnology for drug delivery for pain 179
• Non-injection methods of delivery of analgesics 179
• Topical applications for pain 180
• Topical local anesthetics 180
• Topical NSAIDs 180
• Topical and transdermal diclofenac 181
• Topical application for postoperative pain 181
• Needle-free drug delivery for pain 182
• Transdermal drug delivery for pain 182
• Relief of pain associated with minor medical procedures 182
• Transdermal fentanyl 183
• Transdermal ketoprofen 184
• Transdermal nitroglycerine as an adjuvant to opioids 185
• Transdermal buprenorphine 185
• Transdermal trans-capsaicin 185
• Powder Injection Systems 185
• Intranasal delivery of analgesics 186
• Intranasal morphine 186
• Intranasal morphine derivatives 187
• Intranasal fentanyl 187
• Intranasal buprenorphine 188
• Intranasal ketamine 188
• Intranasal ketorolac 188
• Nasal formulations for migraine 189
• Oral spray formulations for migraine 189
• Delivery of analgesics by inhalation 189
• Buccal transmucosal and sublingual delivery of analgesics 190
• Application for cancer pain 190
• Application for non-cancer pain 191
• Pumps for drug delivery in pain 191
• Patient controlled analgesia 191
• Postoperative pain pumps 192
• Chronogesic (sufentanil) Pain Therapy System 193
• Spinal pumps for delivery of analgesics 193
• Spinal delivery of analgesics 193
• Epidural administration of encapsulated morphine 195
• Epidural dexamethasone 195
• Perispinal etanercept 195
• Intrathecal ziconotide 195
• Intrathecal CGX1160 196
• Intrathecal neostigmine 196
• Intrathecal prostaglandin antagonists 197
• Intrathecal non-NMDA antagonists 197
• Intrathecal fadolmidine 197
• Intrathecal resiniferatoxin 198
• Concluding remarks on intrathecal delivery of analgesic agents 198
• Intracerebroventricular morphine for pain 199
• Development of drug delivery systems for pain therapy 199
• Delivery of analgesics to the CNS across the blood brain barrier 199
• Drug delivery systems in clinical trials 200

6. Drug Development for Pain 203

• Introduction 203
• Drugs in development for pain 203
• Current research goals 204
• The ideal analgesic 204
• Pain R & D goals in the pharmaceutical industry 204
• Drug targets in the spinal cord 205
• Drug targets in the brain 205
• Molecular targets for analgesic drugs 205
• Opioid peptide receptors ligands 205
• Buprenorphine 206
• Nociceptin 207
• Tapentadol 207
• Opioid analgesics acting outside the CNS 207
• Opioid analgesics acting at peripheral receptors 208
• Peripherally acting mu-opioid receptor agonists 208
• Targeting of opioid peptide-containing immune cells 208
• Advantages of peripherally selective opioid drugs 208
• Neuropeptide receptor antagonists for improving the efficacy of opioids 209
• Nicotinic acetylcholine receptors 209
• Mode of action of nACh/neural nicotinic receptor agonists 210
• Potential of central nACh/neural nicotinic receptor agonists 210
• Tumor necrosis factor-α antagonists 211
• Bradykinin antagonists 211
• Newer COX inhibitors 211
• COX-3 inhibitors 212
• Dual cyclooxygenase/lipoxygenase inhibitors 212
• Microsomal prostaglandin E synthase inhibitors 212
• Glutamate receptor antagonists 213
• NMDA receptor modulation for neuropathic pain 213
• Alternatives to direct blocking of NMDA receptors 214
• Glycine antagonists 214
• Metabotropic glutamate receptors 214
• NAALADase inhibitors 215
• α-adrenergic receptor agonists 215
• Norepinephrine transporter inhibition 215
• Ion channels as drug targets 216
• Acid-sensing ion channels as drug target 216
• P2X ion channel receptor antagonists 216
• Voltage-gated sodium channels as analgesic targets 217
• Capsaicin and VR1 receptor-based analgesics 217
• Vanilloid (capsaicin) receptor antagonists 217
• VR1 receptor agonists 218
• TRPV1 antagonists 218
• TRPV1 antagonists in clinical trials 218
• TRPV1-mediated entry of sodium channel blocker QX-314 219
• Substance P and neurokinin receptor antagonists 220
• Adenosine receptor agonists 220
• Targeting prostanoid synthesis 221
• Cholinergic receptor agonists 221
• Nitric oxide-based analgesics 222
• Nitric oxide-releasing NSAIDs 222
• Pharmacology of NO-SAIDs 223
• COX-inhibiting nitric oxide donors 223
• NO-donating structures to extend life cycle of existing analgesics 224
• Nitric oxide mimetics 224
• Neuronal nitric oxide synthase inhibitors 224
• Inhibitors of heme oxygenase 224
• Free radical scavengers as analgesics 225
• Superoxide dismutase mimetics 225
• Ion channels as targets for analgesic drugs 225
• Calcium channel blockers 225
• Sodium channel modulation 226
• GABA analogues 226
• Subtype-selective GABAergic drugs 227
• Cholecystokinin antagonists 227
• CCR2 receptor blockade 227
• Cannabinoids 228
• Cannabinoid receptor agonists 228
• Cannabidiol 230
• Cannabinor 230
• Nabilone 231
• FAAH inhibitors 231
• PF-3845 232
• URB597 232
• Somatostatin analogues 232
• Corticotropin-releasing factor 233
• Tetrodotoxin based analgesics 233
• Conotoxins as analgesics 233
• Substance P-Saporin 234
• Nerve growth factor antagonists 235
• Glial cell line-derived neurotrophic factor 235
• Use of histogranin-like compounds for the management of pain 236
• Activation of P2X7 receptors 236
• Cell and gene therapies for pain 236
• Cell therapy 237
• Implantation of chromaffin cells 237
• Role of stem cells in management of pain 238
• Implantation of astrocytes secreting enkephalin 238
• Cells for delivery of antinociceptive molecules 238
• Implantation of genetically engineered cells 239
• Cell therapy for low back pain 239
• Cell therapy for knee pain due to degenerative disorders 240
• Cell therapy for peripheral neuropathy 240
• Concluding remarks on cell therapy for pain 240
• Gene therapy 241
• Rationale of gene therapy for pain 241
• Vectors for gene therapy of pain 242
• Methods of gene delivery for pain 242
• Gene delivery by intrathecal route 243
• Vectors for endogenous analgesic production in cranial neuralgias 243
• Gene delivery by intrathecal route 243
• Gene transfer to the dorsal nerve roots 244
• Gene therapy of peripheral neuropathy 245
• Gene transfer by injections into the brain substance 245
• Zinc finger DNA-binding protein therapeutic for chronic pain 245
• Gene therapy for producing enkephalin to block pain signals 246
• Targeting nuclear factor-kβ 247
• Gene therapy targeted to neuroimmune component of chronic pain 247
• Antisense therapy for pain 247
• siRNA for relief of neuropathic pain 248
• Potential applications of gene therapy for management of pain 248
• Concluding remarks about gene therapy for pain 249
• Preclinical development of pain drugs 249
• NGF-blocking antibody 250
• Prostatic acid phosphatase as a novel analgesic 250
• Preclinical development of drugs for neuropathic pain 251
• 5-HT receptor agonists 252
• A-803467 252
• AM1241 252
• Artemin/Neuroblastin 253
• Capsazepine 253
• Central nACh receptor agonists 254
• CGP 35024 254
• Drugs that suppress glial activation 254
• Erythropoietin 255
• Gene therapy for neuropathic pain 255
• NCX 8001 255
• NR2B subtype NMDA receptor ligands 256
• NW-1029 256
• R116301 256
• Targeting tumor necrosis factor 257
• Future targets for osteoarthritic pain 257
• Pain drugs in clinical trials 257
• Clinical trials of miscellaneous drugs for pain 258
• Alvimopan 259
• Asimadoline 260
• EN3202 260
• Oxytrex 260
• Drugs in clinical trials for postsurgical pain 261
• Bicifadine 262
• DepoMorphine 262
• TC-2696 263
• Cox-2 inhibitors in clinical trials 263
• Clinical trials of disease modifying therapies for rheumatoid arthritis 264
• Drugs in clinical development for neuropathic pain 265
• Adenosine A1 agonists for neuropathic pain 267
• Botulinum toxin type A 268
• CPL7075 268
• D-amino acid oxidase inhibitors 269
• Glyx-13 269
• IP-751 269
• Lacosamide 270
• Oxcarbazepine 270
• Perampanel 270
• Ralfinamide 270
• Retigabine 271
• SB-509 271
• SCP-1 271
• TC-6499 271
• Tebanicline 272
• Tezampanel 272
• Thalidomide 272
• TRO19622 273
• V3381 273
• XP-13512 273
• Zonisamide 274
• Drug discovery and development for migraine 274
• Drugs in clinical development for migraine 274
• Drug development for visceral pain 277

7. Legal and regulatory issues of pain management 279

• Pain relief as a legal right 279
• Pain relief and the WHO 279
• Regulatory issues 279
• Opioids and cannabinoids 279
• DEA and use of opioids for pain relief in terminal care 279
• FDA and COX-2 inhibitors 280
• Legal issues of COX-2 inhibitors 281
• Misuse of analgesics 281
• Opioids and regulatory agencies 281
• Misuse of fentanyl 281

8. Pain Markets 283

• Introduction 283
• Epidemiological basis of pain markets 283
• Cancer 284
• Neuropathic pain 284
• Trigeminal neuralgia 284
• Arthritis 284
• Backache 284
• Migraine 285
• Multiple sclerosis 285
• Irritable bowel syndrome 285
• Chronic pelvic pain 285
• Chronic pain due to traumatic brain injury 285
• Postsurgical pain 286
• Economics of pain 286
• Pain as a driver of healthcare costs 286
• Disability and financial loss through pain 287
• Pain markets based on painful conditions 287
• The cancer pain market 287
• The arthritis pain market 288
• Postsurgical pain market 288
• The backache market 288
• The headache market 289
• Neuropathic pain market 289
• Fibromyalgia market 290
• Pain markets based on drugs 290
• Opioids 290
• Nonsteroidal antiinflammatory drugs 290
• Transdermal pain therapeutics 291
• Anesthesia 291
• Antiepileptic drugs as analgesics 291
• Other drugs 292
• Hospital vs retail share of pain market 292
• Hospital versus retail opioid market 292
• Devices for pain 292
• Pain markets according to geographical areas 292
• Cost effectiveness of various approaches 293
• Unfulfilled R&D needs in pain therapy 293
• Under treatment of pain 293
• Unfulfilled needs in drug development for chronic pain 294
• Strategies for developing pain markets 294
• Finding alternatives to intrathecal administration for chronic pain 295
• Development of other applications of analgesic drugs 295
• Partnership of patients, pharmacists and companies 296
• Factors that may influence future pain markets 296
• Drivers of pain markets 296
• Public surveys as indicators of impact of pain on people 296
• Effect of regulatory reviews on markets for pain products 297
• Novel versus older therapies for pain 297

9. Future of Pain Therapeutics 299

• Introduction 299
• Advances in the understanding of pain 299
• Pathogenesis of chronic pain 299
• Role of glia in neuropathic pain 299
• Molecular and neurobiological techniques 300
• Improved understanding of cancer pain 301
• Advances in drug discovery and development for pain 301
• Novel targets for drug discovery for pain 301
• PTH2 receptor 301
• Modulators of endogenous cannabinoids 302
• Application of new technologies to pain therapeutics 302
• Application of nanobiotechnology to pain therapeutics 303
• Technologies for the manufacture of analgesics 304
• Future trends and needs in pain management 304
• Pain management in future healthcare systems 305
• Systems biology approach to pain 305
• Personalized pain management 306
• Pharmacogenomics and pharmacogenetics of pain 307
• Genetic mutations associated with reduced response to analgesics 308
• Genetic mutations with loss of pain 308
• Mechanism-specific management of pain 309
• Preoperative testing to tailor postoperative analgesic requirements 309
• Strategies for improving pain management 309

10. Companies Involved in Pain Therapeutics 311

• Introduction 311
• Profiles of companies 311
• Collaborations 479

11. References 485

Tables

• Table 1 1: Landmarks in the history of pain therapeutics 22
• Table 1 2: Classification of chronic pain 24
• Table 1 3: Classification of neuropathic pain 26
• Table 1 4: Classification of chronic cancer pain according to cause 27
• Table 1 5: Percentage of patients with pain according to the type of cancer 28
• Table 1 6: Key molecular elements of pain in the peripheral nervous system 48
• Table 1 7: Key molecular elements of pain in the central nervous system 49
• Table 2 1: IASP guidelines for the use of animals in pain studies 60
• Table 2 2: Chronic pain as a manifestation of other diseases 61
• Table 2 3: Recommendations for assessing patient satisfaction with pain management 66
• Table 3 1: Classification of some currently used pain medications according to mechanism 73
• Table 3 2: Drugs used for the treatment of pain 73
• Table 3 3: Selective COX-2 inhibitors in clinical use for pain 75
• Table 3 4: Antiepileptic drugs with analgesic effect 88
• Table 3 5: Companies developing products to deter abuse of opioids 97
• Table 4 1: Non-pharmacological approaches to management of pain 102
• Table 4 2: Companies involved in neuromodulation therapy for pain 108
• Table 4 3: Reasons for the inadequate management of acute pain 110
• Table 4 4: Causes of chronic backache 125
• Table 4 5: Management of chronic pelvic pain 128
• Table 4 6: Management of pain in cancer 129
• Table 4 7: Definitions of tolerance, physiological dependence, withdrawal and addiction 134
• Table 4 8: A simplified classification of headache 135
• Table 4 9: Various methods for the management of migraine 136
• Table 4 10: Management of neuropathic pain based on mechanism and diagnosis 144
• Table 4 11: Management of central neuropathic pain 148
• Table 4 12: Current management of peripheral diabetic neuropathy 151
• Table 4 13: Treatment strategies for postherpetic neuralgia 152
• Table 4 14: Management of complex regional pain syndrome 154
• Table 4 15: Methods of treating phantom limb pain 157
• Table 4 16: Anti-itching therapies 163
• Table 4 17: Suggested improvements in the management of pain 172
• Table 5 1: A classification of drug delivery methods used in management of pain 175
• Table 5 2: Selected marketed non-injection drug delivery systems for pain 179
• Table 5 3: Spinal administration of drugs for pain 194
• Table 5 4: Selected drug delivery systems for pain in clinical development 200
• Table 6 1: Classification of drugs in development for pain 203
• Table 6 2: Major opioids receptors and their ligands 206
• Table 6 3: Types of TRPV1 antagonists 218
• Table 6 4: TRPV1 antagonists in clinical trials 219
• Table 6 5: Strategies to counteract pain at various levels at periphery and in the CNS 221
• Table 6 6: NO-related therapies for pain 222
• Table 6 7: Cannabinoid receptor agonists in clinical development as analgesics 229
• Table 6 8: Preclinical studies on cannabinoid (CB2) receptor agonists as analgesics 230
• Table 6 9: Experimental gene therapy approaches for relief of pain 242
• Table 6 10: Selected preclinical approaches to pain therapy 250
• Table 6 11: Selected preclinical drugs for neuropathic pain 251
• Table 6 12: Selected clinical trials of miscellaneous drugs for pain 258
• Table 6 13: Selected clinical trials of drugs for postsurgical pain 261
• Table 6 14: COX-2 inhibitors in clinical development 263
• Table 6 15: Disease modifying antirheumatic drugs in clinical trials 264
• Table 6 16: Clinical trials of drugs for neuropathic pain 265
• Table 6 17: Selected drugs in clinical development for migraine 274
• Table 6 18: Therapeutic targets for treating visceral pain 277
• Table 8 1: Market values for various painful conditions 2008-2018 287
• Table 8 2: Changes in market shares of drugs for neuropathic pain 2008-2018 289
• Table 8 3: Markets for pain according to therapies 2008-2018 290
• Table 8 4: Distribution of value of pain therapeutics in major markets 2008-2018 293
• Table 8 5: Distribution of value of opioids in major pain markets 2008-2018 293
• Table 8 6: Distribution of value of NSAIDs in major pain markets 2008-2018 293
• Table 8 7: Strategies for developing pain markets 295
• Table 9 1: P450 isoforms in the metabolism of drugs used in the management of pain 307
• Table 10 1: Product pipeline of Adolor Corporation 317
• Table 10 2: Endo Pharmaceuticals' products in clinical trials 372
• Table 10 3: Selected collaborations in the area of pain management 479

Figures

• Figure 1 1: Afferent pain pathways 30
• Figure 1 2: Evolution of the gate control theory 32
• Figure 1 3: The body self-neurometric 33
• Figure 1 4: Various ligands and receptors on the peripheral terminals of nociceptive nerve fibers 49
• Figure 1 5: Prostaglandin biosynthesis pathway 52
• Figure 2 1: Biopsychosocial factors that interact and modulate the experience of pain 62
• Figure 2 2: Pain intensity scales 63
• Figure 4 1: The WHO step ladder for pain 130
• Figure 4 2: An algorithm for the acute management of migraine 137
• Figure 4 3: Neuroimmune activation events leading to sensitization of CNS 143
• Figure 4 4: An algorithm for the management of peripheral neuropathic pain 156
• Figure 4 5: Algorithm for management of patients with chronic pain and depression 160
• Figure 5 1: Powder Injection Systems 186
• Figure 6 1: Attributes of the ideal analgesic 204
• Figure 6 2: Nerve targeting drug delivery system for gene therapy of pain 246
• Figure 8 1: Unfulfilled needs in the treatment for chronic pain 294
• Figure 9 1: Impact of new technologies on pain therapeutics 303
• Figure 9 2: A scheme of personalized management of pain 306