疼痛治療：藥品・市場・企業

Abstract

Summary

This report describes the latest concepts of pathomechanisms of pain as a basis for management and development of new pharmacotherapies for pain. Major segments of the pain market are arthritis, neuropathic pain and cancer pain. Because pain is a subjective sensation, it is difficult to evaluate objectively in clinical trials. Various tools for pain measurement are described, including brain imaging.

Most of the currently used analgesic drugs fall into the categories of opioids and nonsteroidal antiinflammatory drugs such as COX-2 inhibitors. Non-opioid analgesics include ketamine, a N-methyl-D-aspartate receptor antagonist. Adjuvant analgesics include antidepressants and antiepileptic drugs used for the treatment of neuropathic pain. Management of pain is multidisciplinary and includes both pharmacological and non-pharmacological methods such as acupuncture, transcutaneous electrical nerve stimulation and surgery. Various pain syndromes require different approaches in management, for example, the main category of drugs for migraine are triptans such as sumatriptan.

Drug delivery is an important consideration in pain treatment. Controlled release preparations provide a steady delivery of analgesics. Well-known non-injection methods such astransdermal, pulmonary and intranasal application have been used. Topical analgesics and local anesthetics are also available. Devices such as implanted pumps are used for delivery of drugs such as opioids intrathecally (introduction into spinal subarachnoid space by lumbar puncture) in patients with cancer pain.

The wide variety of drugs in development includes opioid receptor ligands, bradykinin antagonists, mPGES-1 inhibitors, glutamate receptor antagonists, substance P and neurokinin receptor antagonists, norepinephrine transporter inhibitors,P2X2 neuron receptor antagonists and nitric oxide-based analgesics. A number of cannabinoids are also in development for pain. Fish-derived tetrodotoxin was initially focused on indication of opiate addiction withdrawal but is found to have an analgesic action as well. Cone shells contain therapeutically useful peptides including the conotoxins, and one such peptide, ziconotide, has been approved. Various cell and gene therapies are also being developed for the management of pain.

Advances in molecular and biological techniques are markedly advancing our undestanding of pain. Understanding the pathophysiology of pain is an important factor in discovery of rational therapies for pain. Advances in pharmacogenomics and pharmacogenetics are enabling the development of personalized approaches to the management of pain.

Over 500 companies have been identified to be involved in developing or marketing pain therapeutics and 154 of these are profiled in the report along with 142 collaborations. These are a mix of pharmaceutical companies and biotechnology companies.

The worldwide analgesic markets were analyzed for the year 2008 and projected to 2018. Calculations are based on the epidemiology of various painful conditions and the development of analgesic drugs and devices. Unfulfilled needs for analgesics are identified and strategies are outlined to develop markets for analgesic drugs.The report is supplemented with 65 tables, 18 figures, and 500 selected references to the literature.

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 26
• Bone pain in cancer 28
• Complex regional pain syndrome 29
• Mechanisms of pain 29
• 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
• 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
• 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 90
• Pregabalin 91
• Topiramate 92
• Valproic acid 92
• Other antiepileptic drugs 92
• Clonidine 92
• 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 95
• Gastrointestinal adverse effects of NSAIDs 95
• Measures to reduce gastrointestinal adverse effects of NSAIDs 96
• Cardiovascular adverse effects of COX-2 inhibitors 96
• Adverse effects of opioids 96
• 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 98
• Opioid-associated constipation 98
• Approaches to reduce adverse effects of opioids 99
• PEGylated naloxol 99
• Innovative approaches to modify opioid pharmacology 99
• Adverse effects of non-narcotic analgesics 99
• 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 114
• Chronic abdominal pain 115
• Functional somatic syndromes 115
• Fibromyalgia syndrome 115
• Pathomechanism of FMS 116
• Management of FMS 116
• New developments in pharmacotherapy of FMS 117
• Erythromelalgia 117
• Irritable bowel syndrome 118
• Opioids for IBS 119
• Tricyclic antidepressants for IBS 119
• Serotonin-modulating drugs for IBS 119
• Musculoskeletal pain 120
• Myofascial pain syndrome 120
• Osteoarthritis 120
• Pathomechanism of osteoarthritis 120
• Pain aggravates osteoarthritis by crosstalk between CNS and the joint 121
• Management of osteoarthritis 122
• Rheumatoid arthritis 123
• Management of pain in rheumatoid arthritis 123
• Disease modifying therapies in rheumatoid arthritis 123
• Resurgence of interest in gold-based treatments for RA 124
• Backache 125
• Use of analgesics for management of back pain 125
• Miscellaneous medical therapies for backache and sciatica 126
• Neck pain 127
• Chronic pelvic pain 127
• Prostatitis 128
• Cancer pain 128
• Opioid treatment of cancer pain 129
• Breakthrough and opioid-insensitive pains 130
• Methods of delivery of opioids for cancer pain 130
• Implantation of drug delivery devices 131
• Management of bone pain in cancer 131
• Use of non-opioid analgesics for cancer pain 132
• Adjuvant drugs for cancer pain 132
• Radiation therapy 132
• Alternative non-pharmacological methods 132
• Anesthetic techniques 132
• Surgical methods of cancer pain relief 133
• Conclusions regarding management of cancer pain 133
• Chronic non-malignant pain 133
• Headache 134
• Migraine 134
• Management of acute migraine 135
• Neurostimulation for migraine 138
• Transcranial magnetic stimulation for migraine 139
• Migraine prophylaxis 140
• Cluster headache 140
• Tension headache 140
• Chronic daily headache 141
• Trigeminal neuralgia 141
• Dental pain 142
• Neuropathic pain 142
• Pathogenesis of neuropathic pain 142
• Chronobiology of neuropathic pain as guide to therapy 143
• Management of neuropathic pain based on mechanism 143
• Guidelines for the management of neuropathic pain 144
• Pharmacotherapy of neuropathic pain 144
• Evidence-based management of neuropathic pain 146
• Management of central neuropathic pain 147
• Neurosurgical approaches to central neuropathic pain 147
• Management of neuropathic pain in syringomyelia 148
• Neuropathic pain associated with spinal cord injury 148
• Peripheral neuropathic pain 148
• Management of postsurgical peripheral neuropathic pain 149
• Management of chemotherapy-induced pain 149
• Morton' s neuroma 149
• Management of peripheral diabetic neuropathy 150
• Postherpetic neuralgia 151
• Complex regional pain syndrome 153
• An algorithm for the management of peripheral neuropathic pain 155
• Phantom limb pain 155
• Pathomechanism of phantom limb pain 155
• Management of phantom limb pain 156
• Pain and depression 158
• Neurochemical link between pain and depression 159
• Management of chronic pain and depression 159
• Miscellaneous painful conditions 160
• Burning mouth syndrome 160
• Chronic unstable angina 160
• Mastalgia 161
• Ophthalmic pain 161
• Pain in Parkinson' s disease 161
• Management of itching 162
• Topical applications for itching 162
• Systemic therapies for itching 163
• Non-pharmacological therapies for itch 164
• Management of pain in special population groups 164
• Racial and ethnic differences in pain management 164
• Pain in neonates 164
• Management of pain in children 165
• Management of pain in the elderly 165
• Management of pain in women 167
• Reasons for increased pain perception in women 167
• Chronic pelvic pain in women 167
• Gender differences in response to analgesics 167
• Considerations for pain management in women 168
• Management of pain in neurologically handicapped persons 168
• Management of pain in the cognitively impaired elderly people 168
• Management of pain in brain-damaged minimally conscious patients 169
• Management of pain in the terminally ill 169
• Deficiencies in the management of pain 170
• Negative physician attitudes in pain management 170
• Suggestions for improvement of pain management by healthcare providers 171
• Pain as the fifth vital sign 172
• Multidisciplinary approaches to pain management 172

5. Drug Delivery for Pain 173

• Introduction 173
• Intra-articular injection for relief of joint pain 174
• Controlled release drug delivery for pain 174
• Accelerating the effect of subcutaneous morphine 174
• Controlled drug delivery at site of pain 174
• Oral extended release opioids 175
• Extended release oral morphine 175
• Controlled release oxycodone 175
• Extended release oxymorphone 176
• Oral extended release tramadol 176
• Extended release gabapentin 177
• Use of nanotechnology for drug delivery for pain 177
• Non-injection methods of delivery of analgesics 177
• Topical applications for pain 178
• Topical local anesthetics 178
• Topical NSAIDs 178
• Topical and transdermal diclofenac 179
• Topical application for postoperative pain 179
• Needle-free drug delivery for pain 180
• Transdermal drug delivery for pain 180
• Relief of pain associated with minor medical procedures 180
• Transdermal fentanyl 180
• Transdermal ketoprofen 182
• Transdermal nitroglycerine as an adjuvant to opioids 183
• Transdermal buprenorphine 183
• Transdermal trans-capsaicin 183
• Powder Injection Systems 183
• Intranasal delivery of analgesics 184
• Intranasal morphine 184
• Intranasal diamorphine 185
• Intranasal fentanyl 185
• Intranasal buprenorphine 185
• Intranasal ketamine 186
• Intranasal ketorolac 186
• Nasal formulations for migraine 186
• Oral spray formulations for migraine 187
• Delivery of analgesics by inhalation 187
• Buccal transmucosal and sublingual delivery of analgesics 188
• Application for cancer pain 188
• Application for non-cancer pain 188
• Pumps for drug delivery in pain 189
• Patient controlled analgesia 189
• Postoperative pain pumps 189
• Chronogesic (sufentanil) Pain Therapy System 190
• Spinal pumps for delivery of analgesics 191
• Spinal delivery of analgesics 191
• Epidural administration of encapsulated morphine 192
• Epidural dexamethasone 193
• Perispinal etanercept 193
• Intrathecal ziconotide 193
• Intrathecal CGX1160 194
• Intrathecal neostigmine 194
• Intrathecal prostaglandin antagonists 194
• Intrathecal non-NMDA antagonists 195
• Intrathecal fadolmidine 195
• Intrathecal resiniferatoxin 195
• Concluding remarks on intrathecal delivery of analgesic agents 196
• Intracerebroventricular morphine for pain 196
• Development of drug delivery systems for pain therapy 196
• Delivery of analgesics to the CNS across the blood brain barrier 196
• Drug delivery systems in clinical trials 197

6. Drug Development for Pain 199

• Introduction 199
• Drugs in development for pain 199
• Current research goals 200
• The ideal analgesic 200
• Pain R & D goals in the pharmaceutical industry 200
• Drug targets in the spinal cord 201
• Drug targets in the brain 201
• Molecular targets for analgesic drugs 201
• Opioid peptide receptors ligands 201
• Buprenorphine 202
• Nociceptin 203
• Tapentadol 203
• Opioid analgesics acting outside the CNS 203
• Opioid analgesics acting at peripheral receptors 204
• Peripherally acting mu-opioid receptor agonists 204
• Targeting of opioid peptide-containing immune cells 204
• Advantages of peripherally selective opioid drugs 204
• Neuropeptide receptor antagonists for improving the efficacy of opioids 205
• Nicotinic acetylcholine receptors 205
• Mode of action of nACh/neural nicotinic receptor agonists 206
• Potential of central nACh/neural nicotinic receptor agonists 206
• Tumor necrosis factor-α antagonists 207
• Bradykinin antagonists 207
• Newer COX inhibitors 207
• COX-3 inhibitors 208
• Dual cyclooxygenase/lipoxygenase inhibitors 208
• Microsomal prostaglandin E synthase inhibitors 208
• Glutamate receptor antagonists 209
• NMDA receptor modulation for neuropathic pain 209
• Alternatives to direct blocking of NMDA receptors 210
• Glycine antagonists 210
• Metabotropic glutamate receptors 210
• NAALADase inhibitors 211
• α-adrenergic receptor agonists 211
• Norepinephrine transporter inhibition 211
• Ion channels as drug targets 212
• Acid-sensing ion channels as drug target 212
• P2X ion channel receptor antagonists 212
• Voltage-gated sodium channels as analgesic targets 213
• Capsaicin and VR1 receptor-based analgesics 213
• Vanilloid (capsaicin) receptor antagonists 213
• VR1 receptor agonists 214
• TRPV1 antagonists 214
• TRPV1 antagonists in clinical trials 214
• TRPV1-mediated entry of sodium channel blocker QX-314 215
• Substance P and neurokinin receptor antagonists 216
• Adenosine receptor agonists 216
• Targeting prostanoid synthesis 217
• Cholinergic receptor agonists 217
• Nitric oxide-based analgesics 218
• Nitric oxide-releasing NSAIDs 218
• Pharmacology of NO-SAIDs 219
• COX-inhibiting nitric oxide donors 219
• NO-donating structures to extend life cycle of existing analgesics 220
• Nitric oxide mimetics 220
• Neuronal nitric oxide synthase inhibitors 220
• Inhibitors of heme oxygenase 220
• Free radical scavengers as analgesics 221
• Superoxide dismutase mimetics 221
• Ion channels as targets for analgesic drugs 221
• Calcium channel blockers 221
• Sodium channel modulation 222
• GABA analogues 222
• Subtype-selective GABAergic drugs 223
• Cholecystokinin antagonists 223
• CCR2 receptor blockade 223
• Cannabinoids 224
• Cannabinoid receptor agonists 224
• Cannabidiol 226
• Cannabinor 226
• Nabilone 227
• FAAH inhibitors 227
• PF-3845 228
• URB597 228
• Somatostatin analogues 228
• Corticotropin-releasing factor 229
• Tetrodotoxin based analgesics 229
• Conotoxins as analgesics 229
• Substance P-Saporin 230
• Nerve growth factor antagonists 231
• Glial cell line-derived neurotrophic factor 231
• Use of histogranin-like compounds for the management of pain 232
• Activation of P2X7 receptors 232
• Cell and gene therapies for pain 232
• Cell therapy 233
• Implantation of chromaffin cells 233
• Role of stem cells in management of pain 234
• Implantation of astrocytes secreting enkephalin 234
• Cells for delivery of antinociceptive molecules 234
• Implantation of genetically engineered cells 235
• Cell therapy for low back pain 235
• Cell therapy for knee pain due to degenerative disorders 236
• Cell therapy for peripheral neuropathy 236
• Concluding remarks on cell therapy for pain 236
• Gene therapy 237
• Rationale of gene therapy for pain 237
• Vectors for gene therapy of pain 238
• Methods of gene delivery for pain 238
• Gene delivery by intrathecal route 239
• Vectors for endogenous analgesic production in cranial neuralgias 239
• Gene delivery by intrathecal route 239
• Gene transfer to the dorsal nerve roots 240
• Gene therapy of peripheral neuropathy 241
• Gene transfer by injections into the brain substance 241
• Zinc finger DNA-binding protein therapeutic for chronic pain 241
• Gene therapy for producing enkephalin to block pain signals 242
• Targeting nuclear factor-kβ 243
• Gene therapy targeted to neuroimmune component of chronic pain 243
• Antisense therapy for pain 243
• siRNA for relief of neuropathic pain 244
• Potential applications of gene therapy for management of pain 244
• Concluding remarks about gene therapy for pain 245
• Preclinical development of pain drugs 245
• NGF-blocking antibody 246
• Prostatic acid phosphatase as a novel analgesic 246
• Preclinical development of drugs for neuropathic pain 247
• 5-HT receptor agonists 248
• A-803467 248
• AM1241 248
• Artemin/Neuroblastin 249
• Capsazepine 249
• Central nACh receptor agonists 250
• CGP 35024 250
• Drugs that suppress glial activation 250
• Erythropoietin 251
• Gene therapy for neuropathic pain 251
• NCX 8001 251
• NR2B subtype NMDA receptor ligands 252
• NW-1029 252
• R116301 252
• Targeting tumor necrosis factor 253
• Future targets for osteoarthritic pain 253
• Pain drugs in clinical trials 253
• Clinical trials of miscellaneous drugs for pain 254
• Alvimopan 255
• Asimadoline 256
• EN3202 256
• Oxytrex 256
• Drugs in clinical trials for postsurgical pain 257
• Bicifadine 258
• DepoMorphine 258
• TC-2696 259
• Cox-2 inhibitors in clinical trials 259
• Clinical trials of disease modifying therapies for rheumatoid arthritis 260
• Drugs in clinical development for neuropathic pain 261
• Adenosine A1 agonists for neuropathic pain 263
• Botulinum toxin type A 263
• CPL7075 264
• Glyx-13 264
• IP-751 265
• Lacosamide 265
• Oxcarbazepine 266
• Perampanel 266
• Ralfinamide 266
• Retigabine 266
• SB-509 267
• SCP-1 267
• TC-6499 267
• Tebanicline 267
• Tezampanel 268
• Thalidomide 268
• TRO19622 268
• V3381 269
• XP-13512 269
• Zonisamide 269
• Drug discovery and development for migraine 270
• Drugs in clinical development for migraine 270
• Drug development for visceral pain 273

7. Legal and regulatory issues of pain management 275

• Pain relief as a legal right 275
• Pain relief and the WHO 275
• Regulatory issues 275
• Opioids and cannabinoids 275
• DEA and use of opioids for pain relief in terminal care 275
• FDA and COX-2 inhibitors 276
• Legal issues of COX-2 inhibitors 277
• Misuse of analgesics 277
• Opioids and regulatory agencies 277
• Misuse of fentanyl 277

8. Pain Markets 279

• Introduction 279
• Epidemiological basis of pain markets 279
• Cancer 280
• Neuropathic pain 280
• Trigeminal neuralgia 280
• Arthritis 280
• Backache 280
• Migraine 281
• Multiple sclerosis 281
• Irritable bowel syndrome 281
• Chronic pelvic pain 281
• Chronic pain due to traumatic brain injury 281
• Postsurgical pain 282
• Economics of pain 282
• Pain as a driver of healthcare costs 282
• Disability and financial loss through pain 283
• Pain markets based on painful conditions 283
• The cancer pain market 283
• The arthritis pain market 284
• Postsurgical pain market 284
• The backache market 284
• The headache market 285
• Neuropathic pain market 285
• Fibromyalgia market 286
• Pain markets based on drugs 286
• Opioids 286
• Nonsteroidal antiinflammatory drugs 286
• Transdermal pain therapeutics 287
• Anesthesia 287
• Antiepileptic drugs as analgesics 287
• Other drugs 288
• Hospital vs retail share of pain market 288
• Hospital versus retail opioid market 288
• Devices for pain 288
• Pain markets according to geographical areas 288
• Cost effectiveness of various approaches 289
• Unfulfilled R&D needs in pain therapy 289
• Under treatment of pain 289
• Unfulfilled needs in drug development for chronic pain 290
• Strategies for developing pain markets 290
• Finding alternatives to intrathecal administration for chronic pain 291
• Development of other applications of analgesic drugs 291
• Partnership of patients, pharmacists and companies 292
• Factors that may influence future pain markets 292
• Drivers of pain markets 292
• Public surveys as indicators of impact of pain on people 292
• Effect of regulatory reviews on markets for pain products 293
• Novel versus older therapies for pain 293

9. Future of Pain Therapeutics 295

• Introduction 295
• Advances in the understanding of pain 295
• Pathogenesis of chronic pain 295
• Role of glia in neuropathic pain 295
• Molecular and neurobiological techniques 296
• Improved understanding of cancer pain 297
• Advances in drug discovery and development for pain 297
• Novel targets for drug discovery for pain 297
• PTH2 receptor 297
• Modulators of endogenous cannabinoids 298
• Application of new technologies to pain therapeutics 298
• Application of nanobiotechnology to pain therapeutics 299
• Technologies for the manufacture of analgesics 300
• Future trends and needs in pain management 300
• Pain management in future healthcare systems 301
• Systems biology approach to pain 301
• Personalized pain management 302
• Pharmacogenomics and pharmacogenetics of pain 303
• Genetic mutations with loss of pain 304
• Mechanism-specific management of pain 304
• Preoperative testing to tailor postoperative analgesic requirements 305
• Strategies for improving pain management 305

10. Companies Involved in Pain Therapeutics 307

• Introduction 307
• Profiles of companies 307
• Collaborations 471

11. References 477

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 127
• Table 4 6: Management of pain in cancer 128
• Table 4 7: Definitions of tolerance, physiological dependence, withdrawal and addiction 134
• Table 4 8: A simplified classification of headache 134
• Table 4 9: Various methods for the management of migraine 135
• Table 4 10: Management of neuropathic pain based on mechanism and diagnosis 143
• Table 4 11: Management of central neuropathic pain 147
• Table 4 12: Current management of peripheral diabetic neuropathy 150
• 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 156
• Table 4 16: Anti-itching therapies 162
• 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 173
• Table 5 2: Selected marketed non-injection drug delivery systems for pain 177
• Table 5 3: Spinal administration of drugs for pain 191
• Table 5 4: Selected drug delivery systems for pain in clinical development 197
• Table 6 1: Classification of drugs in development for pain 199
• Table 6 2: Major opioids receptors and their ligands 202
• Table 6 3: Types of TRPV1 antagonists 214
• Table 6 4: TRPV1 antagonists in clinical trials 215
• Table 6 5: Strategies to counteract pain at various levels at periphery and in the CNS 217
• Table 6 6: NO-related therapies for pain 218
• Table 6 7: Cannabinoid receptor agonists in clinical development as analgesics 225
• Table 6 8: Preclinical studies on cannabinoid (CB2) receptor agonists as analgesics 226
• Table 6 9: Experimental gene therapy approaches for relief of pain 238
• Table 6 10: Selected preclinical approaches to pain therapy 246
• Table 6 11: Selected preclinical drugs for neuropathic pain 247
• Table 6 12: Selected clinical trials of miscellaneous drugs for pain 254
• Table 6 13: Selected clinical trials of drugs for postsurgical pain 257
• Table 6 14: COX-2 inhibitors in clinical development 259
• Table 6 15: Disease modifying antirheumatic drugs in clinical trials 260
• Table 6 16: Clinical trials of drugs for neuropathic pain 261
• Table 6 17: Selected drugs in clinical development for migraine 270
• Table 6 18: Therapeutic targets for treating visceral pain 273
• Table 8 1: Market values for various painful conditions 2008-2018 283
• Table 8 2: Changes in market shares of drugs for neuropathic pain 2008-2018 285
• Table 8 3: Markets for pain according to therapies 2008-2018 286
• Table 8 4: Distribution of value of pain therapeutics in major markets 2008-2018 289
• Table 8 5: Distribution of value of opioids in major pain markets 2008-2018 289
• Table 8 6: Distribution of value of NSAIDs in major pain markets 2008-2018 289
• Table 8 7: Strategies for developing pain markets 291
• Table 9 1: P450 isoforms in the metabolism of drugs used in the management of pain 303
• Table 10 1: Product pipeline of Adolor Corporation 311
• Table 10 2: Endo Pharmaceuticals' products in clinical trials 365
• Table 10 3: Selected collaborations in the area of pain management 471

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 129
• Figure 4 2: An algorithm for the acute management of migraine 136
• Figure 4 3: Neuroimmune activation events leading to sensitization of CNS 142
• Figure 4 4: An algorithm for the management of peripheral neuropathic pain 155
• Figure 4 5: Algorithm for management of patients with chronic pain and depression 159
• Figure 5 1: Powder Injection Systems 184
• Figure 6 1: Attributes of the ideal analgesic 200
• Figure 6 2: Nerve targeting drug delivery system for gene therapy of pain 242
• Figure 8 1: Unfulfilled needs in the treatment for chronic pain 290
• Figure 9 1: Impact of new technologies on pain therapeutics 299
• Figure 9 2: A scheme of personalized management of pain 302