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 161 of these are profiled in the report along
with 146 collaborations. These are a mix of pharmaceutical companies and
biotechnology companies.
The worldwide analgesic markets were analyzed for the year 2011 and projected
to 2021. 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 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
- 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 29
- Gate control and neuromatrix theories of pain 30
- Pain mediators 31
- Modulation of pain by pictures associated with social contacts 31
- Modulation of pain by emotions 31
- Role of the sympathetic nervous system in pain 32
- Visceral pain 32
- Pathomechanism of visceral pain 32
- 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 34
- 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 36
- Spinal leptin and neuropathic pain 36
- 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 38
- Clinical aspects of itch 39
- Molecular pathophysiology of pain 39
- Role of ion channels in pain 39
- Acid-sensing ion channels 40
- Calcium channels in pain 40
- P2X3 ion channels 41
- Potassium ion channels 41
- Sodium ion channels in pain 41
- TRP ion channels in pain 43
- Genetic basis of pain 43
- Study of genes in pain 44
- Pain as a channelopathy 45
- Pain in the brain 45
- Neuropathic pain-induced morphological changes in the brain 45
- Change from acute to chronic pain 46
- Descending facilitatory modulation of pain 46
- Development of chronic pain following severe accidental injury 47
- Pain and transcriptional repressor DREAM 47
- Role of neuronal plasticity in pain 47
- 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 49
- Kinins 50
- Serotonin 50
- Substance P 50
- Excitatory amino acids 50
- Role of nitric oxide in pain 51
- Prostaglandins 51
- Endocannabinoids 52
- Protein kinase C 52
- Adenosine and adenosine receptors 53
- Vitamin D and pain 53
- Vanilloid receptor 53
- TRPA1 and TRPV1 receptors 53
- Endothelin-B receptors 55
- Nerve growth factor and pain 55
- Adrenomedullin as a pain-related peptide 55
- Biomarkers of pain 55
- Biomarkers of visceral pain 56
2. Assessment of Pain and Analgesics 58
- Introduction 58
- Animal models of pain 58
- An overview 58
- Selection of animal species as models for pain 58
- Types of noxious stimuli 59
- Animal models of neuropathic pain 59
- Animal models of arthritis 59
- Animal models of peripheral neuropathy 60
- Limitations of current pain models 60
- Biogenic animal model of chronic pain 61
- Ethical issues concerning animal pain models 61
- Medical evaluation of pain 62
- Chronic pain as a manifestation of various diseases 62
- Assessment of pain patients 62
- Medical examination 62
- Measurement of pain 63
- Quantitative sensory testing 64
- Pain measurement tools for neonates and children 65
- Quantitative sensory testing 65
- Psychological assessment of pain 66
- Brain imaging in pain 66
- PET for study of pain 66
- PET correlated with fMRI and evoked potentials 67
- Patient outcomes and quality of life during treatment for chronic pain
67
- Collection and analysis of data on pain patients 68
- Evaluation of analgesics in humans 68
- Early phase clinical trials of analgesics in humans 68
- Design of clinical trials for pain 69
- Assessment of neuropathic pain 70
- Transdermal electrical stimulation for study of chronic pain 70
- Placebo effect in pain 71
- Role of electronic pain recording in determination of the placebo effect
71
- Outcome measures for chronic pain trials 72
- Pain, pain therapies and cognitive function 72
3. Pharmacotherapy of Pain 74
- Introduction 74
- Mechanism of action of currently used pain medications 74
- Non-steroidal antiinflammatory drugs 75
- COX-2 inhibitors 75
- Celecoxib 76
- Metamizole 77
- Nimesulide 77
- Rofecoxib 77
- Valdecoxib 78
- Lumiracoxib 78
- Side effects of COX inhibitors 79
- Innovative COX-2 inhibitors in development 80
- Acetaminophen 81
- Antioxidants as analgesics 81
- Opiates and opioids 82
- Innovations in opioid therapy 82
- Oral transmucosal fentanyl 83
- Use of opioids for chronic non-cancer pain 83
- Opioid receptor modulation for visceral pain 83
- Opiorphin 84
- N-methyl-D-aspartate receptor antagonists 84
- Ketamine 84
- CNS 5161 85
- Triptans for treatment of non-migrainous pain 85
- Capsaicin 85
- NGX-4010 86
- Local anesthetics 86
- Topical application 86
- Nerve blocks 86
- Injection of local anesthetics for analgesia 87
- Ultrasound-guided nerve blocks 87
- Topical salicylates for the treatment of pain 87
- Topical rubefacients for acute and chronic pain in adults 87
- Adjunctive analgesics 88
- Antidepressants 88
- Mechanism of analgesic action of antidepressants 89
- Antiepileptic drugs 90
- Mechanism of action of antiepileptic drugs in neuropathic pain 90
- Carbamazepine 91
- Gabapentin 91
- Lamotrigine 92
- Phenytoin 92
- Pregabalin 93
- Topiramate 94
- Valproic acid 94
- Other antiepileptic drugs 94
- Clonidine 94
- Baclofen 95
- Corticosteroids 95
- Calcitonin 96
- Bisphosphonates 96
- Botulinum toxins 96
- Analgesic effect of botulinum toxin A 97
- Engineered botulinum toxin 97
- Analgesics from traditional medical systems 97
- Herbs and other plants 98
- Analgesics derived from cobra toxin 99
- Adverse effects of analgesics 99
- Gastrointestinal adverse effects of NSAIDs 99
- Measures to reduce gastrointestinal adverse effects of NSAIDs 99
- Cardiovascular adverse effects of COX-2 inhibitors 99
- Adverse effects of opioids 100
- Risk of addiction and development of tolerance 100
- Companies developing products to deter abuse of opioids 100
- Remoxy versus Oxycontin 101
- Hyperalgesia associated with opioids 101
- Respiratory depression 102
- Opioid-associated constipation 102
- Narcotic bowel syndrome 102
- Adverse effects of use of opioids in non-malignant pain 102
- Approaches to reduce adverse effects of opioids 103
- PEGylated naloxol 103
- Innovative approaches to modify opioid pharmacology 103
- Regulatory aspects of opioid abuse, overdose and death 103
- Adverse effects of miscellaneous non-narcotic analgesics 104
- Adverse effects of immunosuppressants used for relief of pain 104
- Adverse effects of acetaminophen 105
4. Management of Pain 106
- Introduction 106
- Sites for pain management 106
- Self-medication at home 106
- Physicians' offices 106
- Major hospitals 106
- Pain centers 107
- Non-pharmacological approaches to pain 107
- Alternative medicine 107
- Acupuncture 108
- Aromatherapy 108
- Self-Controlled Energo Neuro Adaptive Regulation 109
- Behavioral therapy 109
- Cognition and pain 109
- Control over brain activation and pain by using functional MRI 109
- Thermal-grill illusion 110
- Virtual reality therapy 110
- Local application of heat 110
- Transcutaneous nerve stimulation 111
- Transcranial magnetic stimulation 111
- Neurosurgery for pain relief 111
- Ablative procedures on the nervous system 112
- Procedures on peripheral, spinal and cranial nerves 112
- Vagal nerve stimulation for control of pain 112
- Neuromodulation 112
- Spinal cord stimulation 113
- Brain stimulation 114
- Implantation of drug delivery devices 114
- Management of special types of pain 114
- Acute pain 114
- Management of acute renal colic: NSAIDS vs. opioids 114
- Combination of opioids and NSAIDs for acute pain 115
- Reasons for inadequate management of acute pain 115
- Perioperative pain management 115
- Devices for delivery of analgesics in the postoperative period 116
- Drug combination for perioperative pain 117
- Gabapentin for reduction of postoperative pain 117
- Ketamine for perioperative pain 117
- Opioids for perioperative pain 118
- Perioperative pain in neurosurgery 118
- Prolonged duration local anesthesia 119
- Concluding remarks on the management of postoperative pain 119
- Pain in the intensive care unit 120
- Pain associated with sports and exercise 120
- Pain associated with trauma 121
- Chronic abdominal pain 121
- Functional somatic syndromes 121
- Fibromyalgia syndrome 122
- Pathomechanism of FMS 122
- Management of FMS 123
- New developments in pharmacotherapy of FMS 123
- Erythromelalgia 124
- Irritable bowel syndrome 125
- Opioids for IBS 125
- Tricyclic antidepressants for IBS 126
- Serotonin-modulating drugs for IBS 126
- Musculoskeletal pain 126
- Myofascial pain syndrome 127
- Osteoarthritis 127
- Pathomechanism of osteoarthritis 127
- Pain aggravates osteoarthritis by crosstalk between CNS and the joint 128
- Management of osteoarthritis 128
- Rheumatoid arthritis 129
- Management of pain in rheumatoid arthritis 130
- Disease modifying therapies in rheumatoid arthritis 130
- Resurgence of interest in gold-based treatments for RA 131
- Backache 131
- Use of analgesics for management of back pain 132
- Miscellaneous medical therapies for backache and sciatica 133
- Neck pain 134
- Chronic pelvic pain 134
- Prostatitis 135
- Cancer pain 135
- Opioid treatment of cancer pain 135
- Breakthrough and opioid-insensitive pains 137
- Morphine-induced enhancement of cancer growth and its prevention 137
- Methods of delivery of opioids for cancer pain 137
- Implantation of drug delivery devices 138
- Management of bone pain in cancer 138
- Use of non-opioid analgesics for cancer pain 139
- Adjuvant drugs for cancer pain 139
- Radiation therapy 140
- Alternative non-pharmacological methods 140
- Anesthetic techniques 140
- Surgical methods of cancer pain relief 140
- Conclusions regarding management of cancer pain 140
- Chronic non-malignant pain 141
- Headache 141
- Migraine 142
- Management of acute migraine 142
- Neurostimulation for migraine 146
- Transcranial magnetic stimulation for migraine 147
- Migraine prophylaxis 147
- Cluster headache 148
- Paroxysmal hemicrania 148
- Tension headache 148
- Chronic daily headache 149
- Trigeminal neuralgia 149
- Dental pain 150
- Neuropathic pain 150
- Pathogenesis of neuropathic pain 150
- Chronobiology of neuropathic pain as guide to therapy 151
- Management of neuropathic pain based on mechanism 152
- Guidelines for the management of neuropathic pain 152
- Pharmacotherapy of neuropathic pain 152
- Evidence-based management of neuropathic pain 155
- Management of central neuropathic pain 155
- Neurosurgical approaches to central neuropathic pain 155
- Management of neuropathic pain in syringomyelia 156
- Neuropathic pain associated with spinal cord injury 156
- Peripheral neuropathic pain 157
- Management of postsurgical peripheral neuropathic pain 157
- Management of chemotherapy-induced pain 157
- Morton's neuroma 158
- Management of peripheral diabetic neuropathy 158
- Postherpetic neuralgia 160
- Complex regional pain syndrome 162
- An algorithm for the management of peripheral neuropathic pain 163
- Phantom limb pain 164
- Pathomechanism of phantom limb pain 164
- Management of phantom limb pain 164
- Pain and depression 166
- Neurochemical link between pain and depression 167
- Management of chronic pain and depression 167
- Miscellaneous painful conditions 168
- Burning mouth syndrome 168
- Chronic unstable angina 169
- Mastalgia 169
- Ophthalmic pain 169
- Pain in Parkinson's disease 170
- Management of chronic unexplained pain 170
- Management of itching 170
- Topical applications for itching 171
- Systemic therapies for itching 172
- Non-pharmacological therapies for itch 173
- Management of pain in special population groups 173
- Racial and ethnic differences in pain management 173
- Pain in neonates 173
- Management of pain in children 174
- Management of pain in the elderly 174
- Management of pain in women 176
- Reasons for increased pain perception in women 176
- Chronic pelvic pain in women 176
- Gender differences in response to analgesics 176
- Considerations for pain management in women 177
- Management of pain in neurologically handicapped persons 177
- Management of pain in the cognitively impaired elderly people 178
- Management of pain in brain-damaged minimally conscious patients 178
- Management of pain in the terminally ill 179
- Problems in the management of pain 179
- Inadequate pain management 179
- Regulation of use of opioids 180
- Suggestions for improvement of pain management by healthcare providers
180
- Pain as the fifth vital sign 182
- Management of neuropathic pain in patients refractory to first line
treatment 182
- Multidisciplinary approaches to pain management 182
5. Drug Delivery for Pain 183
- Introduction 183
- Intra-articular injection for relief of joint pain 184
- Controlled release drug delivery for pain 184
- Accelerating the effect of subcutaneous morphine 184
- Controlled drug delivery at site of pain 184
- Oral extended release opioids 185
- Extended release oral morphine 185
- Controlled release oxycodone 186
- Extended release oxymorphone 186
- Oral extended release tramadol 186
- Extended release gabapentin 187
- Use of nanotechnology for drug delivery for pain 187
- Non-injection methods of delivery of analgesics 187
- Topical applications for pain 188
- Topical local anesthetics 188
- Topical NSAIDs 188
- Topical and transdermal diclofenac 189
- Topical application for postoperative pain 189
- Needle-free drug delivery for pain 190
- Glide SDIR solid dose injector 190
- SUMAVEL"! DosePro"! needle-less injection 190
- Transdermal drug delivery for pain 190
- Relief of pain associated with minor medical procedures 190
- Transdermal fentanyl 191
- Transdermal ketoprofen 192
- Transdermal nitroglycerine as an adjuvant to opioids 193
- Transdermal buprenorphine 193
- Transdermal trans-capsaicin 193
- Powder Injection Systems 194
- Intranasal delivery of analgesics 194
- Intranasal morphine 195
- Intranasal morphine derivatives 195
- Intranasal fentanyl 196
- Intranasal buprenorphine 196
- Intranasal ketamine 196
- Intranasal ketorolac 197
- Nasal formulations for migraine 197
- Oral spray formulations for migraine 197
- Delivery of analgesics by inhalation 198
- Buccal transmucosal and sublingual delivery of analgesics 199
- Application for cancer pain 199
- Application for non-cancer pain 199
- Pumps for drug delivery in pain 200
- Patient controlled analgesia 200
- Postoperative pain pumps 200
- Chronogesic (sufentanil) Pain Therapy System 201
- Spinal pumps for delivery of analgesics 202
- Spinal delivery of analgesics 202
- Epidural administration of analgesics 203
- Epidural dexamethasone 203
- Epidural etanercept 204
- Epidural morphine 204
- Intrathecal administration of analgesics 204
- Intrathecal CGX1160 204
- Intrathecal fadolmidine 204
- Intrathecal lidocaine 205
- Intrathecal neostigmine 205
- Intrathecal non-NMDA antagonists 205
- Intrathecal prostaglandin antagonists 205
- Intrathecal resiniferatoxin 206
- Intrathecal ziconotide 206
- Concluding remarks on intrathecal delivery of analgesic agents 207
- Intracerebroventricular morphine for pain 207
- Development of drug delivery systems for pain therapy 207
- Delivery of analgesics to the CNS across the blood brain barrier 208
- Drug delivery systems in clinical trials 208
6. Drug Development for Pain 211
- Introduction 211
- Drugs in development for pain 211
- Current research goals 212
- The ideal analgesic 212
- Pain R & D goals in the pharmaceutical industry 212
- Drug targets in the spinal cord 213
- Drug targets in the brain 213
- Molecular targets for analgesic drugs 213
- Activation of P2X7 receptors 213
- Adenosine receptor agonists 214
- Alfa2-adrenergic receptor agonists 214
- Anti-NGF strategies 214
- Bradykinin antagonists 215
- Cannabinoids 215
- Cannabinoid receptor agonists 216
- Cannabidiol 217
- Cannabinor 218
- Nabilone 218
- Capsaicin and VR1 receptor-based analgesics 219
- Vanilloid (capsaicin) receptor antagonists 219
- VR1 receptor agonists 219
- CCR2 receptor blockade 220
- Cholecystokinin antagonists 220
- Cholinergic receptor agonists 220
- Conotoxins as analgesics 221
- Corticotropin-releasing factor 222
- FAAH inhibitors 222
- PF-3845 223
- URB597 223
- Free radical scavengers as analgesics 223
- Superoxide dismutase mimetics 224
- GABA analogues 224
- Subtype-selective GABAergic drugs 224
- Glial cell line-derived neurotrophic factor 225
- Glutamate receptor antagonists 225
- NMDA receptor modulation for neuropathic pain 225
- Alternatives to direct blocking of NMDA receptors 226
- Glycine antagonists 226
- Metabotropic glutamate receptors 226
- Histogranin-like compounds for the management of pain 227
- Ion channels as targets for analgesic drugs 227
- Acid-sensing ion channels as drug target 227
- Calcium channel blockers 228
- P2X ion channel receptor antagonists 228
- Sodium channel modulation 229
- Mas-related GPCR agonists 229
- Microsomal prostaglandin E synthase inhibitors 230
- NAALADase inhibitors 231
- Nerve growth factor antagonists 231
- Newer COX inhibitors 231
- COX-3 inhibitors 232
- Dual cyclooxygenase/lipoxygenase inhibitors 232
- Neuropeptide receptor antagonists for improving the efficacy of opioids
232
- Nicotinic acetylcholine receptors 232
- Mode of action of nACh/neural nicotinic receptor agonists 233
- Potential of central nACh/neural nicotinic receptor agonists 233
- Nitric oxide-based analgesics 234
- Nitric oxide-releasing NSAIDs 234
- Pharmacology of NO-SAIDs 235
- COX-inhibiting nitric oxide donors 235
- NO-donating structures to extend life cycle of existing analgesics 236
- Nitric oxide mimetics 236
- Neuronal nitric oxide synthase inhibitors 236
- Norepinephrine transporter inhibition 236
- Opioid peptide receptors ligands 237
- Opioids with unique receptor characteristics 238
- Buprenorphine 238
- Nociceptin 238
- Tapentadol 239
- Opioid analgesics acting outside the CNS 239
- Opioid analgesics acting at peripheral receptors 239
- Peripherally acting mu-opioid receptor agonists 240
- Targeting of opioid peptide-containing immune cells 240
- Advantages of peripherally selective opioid drugs 240
- Resolvins 241
- Somatostatin analogs 241
- Substance P and neurokinin receptor antagonists 241
- Substance P-Saporin 242
- Targeting prostanoid synthesis 242
- Tetrodotoxin based analgesics 243
- TRPV1 antagonists 243
- TRPV1 antagonists in clinical trials 244
- TRPV1-mediated entry of sodium channel blocker QX-314 245
- Tumor necrosis factor-α antagonists 245
- Biological therapies for pain 245
- Cell therapy for pain 246
- Implantation of chromaffin cells 247
- Role of stem cells in management of pain 247
- Implantation of astrocytes secreting enkephalin 248
- Cells for delivery of antinociceptive molecules 248
- Implantation of genetically engineered cells 248
- Cell therapy for low back pain 249
- Cell therapy for knee pain due to degenerative disorders 250
- Cell therapy for peripheral neuropathic pain 250
- Concluding remarks on cell therapy for pain 250
- Gene therapy for pain 251
- Rationale of gene therapy for pain 251
- Gene therapy of peripheral neuropathy 251
- Gene therapy targeted to neuroimmune component of chronic pain 252
- Methods of gene delivery for pain 252
- Vectors for gene therapy of pain 253
- Vectors for endogenous analgesic production in cranial neuralgias 253
- Methods of gene delivery for pain 254
- Gene delivery by intrathecal route 254
- Gene transfer to the dorsal nerve roots 254
- Gene transfer by injections into the brain substance 255
- Antisense therapy for pain 255
- RNAi-based approaches for pain therapy 256
- Potential applications of gene therapy for management of pain 257
- Gene therapy for producing enkephalin to block pain signals 257
- Gene therapy for upregulation of BMP in backache 258
- Gene therapy for targeting nuclear factor-kΒ 259
- Gene therapy for neuropathic pain 259
- Zinc finger DNA-binding protein therapeutic for chronic pain 259
- Concluding remarks about gene therapy for pain 259
- Preclinical development of pain drugs 260
- NGF-blocking antibody 261
- Prostatic acid phosphatase as a novel analgesic 261
- Preclinical development of drugs for neuropathic pain 261
- 5-HT receptor agonists 263
- A-803467 263
- AM1241 263
- Artemin/Neuroblastin 263
- Capsazepine 264
- Central nACh receptor agonists 264
- CGP 35024 265
- Drugs that suppress glial activation 265
- Erythropoietin 265
- NCX 8001 266
- NR2B subtype NMDA receptor ligands 266
- NW-1029 266
- R116301 267
- Targeting tumor necrosis factor 267
- Future targets for osteoarthritic pain 267
- Pain drugs in clinical trials 267
- Clinical trials of miscellaneous drugs for pain 268
- Alvimopan 270
- Asimadoline 270
- EN3202 270
- Oxytrex 270
- Drugs in clinical trials for postsurgical pain 271
- Bicifadine 272
- DepoMorphine 272
- Cox-2 inhibitors in clinical trials 273
- Clinical trials of disease modifying therapies for arthritis 273
- Drugs in clinical development for neuropathic pain 275
- Adenosine A1 agonists for neuropathic pain 277
- AVP-923 (dextromethorphan + quinidine) 278
- Botulinum toxin type A 278
- CNV1014802 278
- CPL7075 278
- D-amino acid oxidase inhibitors 279
- Glyx-13 279
- IP-751 279
- Lacosamide 280
- Oxcarbazepine 280
- Perampanel 280
- Ralfinamide 281
- Retigabine 281
- SB-509 281
- SCP-1 281
- TC-6499 282
- Tebanicline 282
- Tezampanel 282
- Thalidomide 283
- TRO19622 283
- V3381 (indantadol) 283
- XP-13512 284
- Zonisamide 284
- Drug discovery and development for migraine 284
- Drugs in clinical development for migraine 285
- Clinical development of preventive therapies for migraine 287
- Drug development for visceral pain 288
7. Legal and regulatory issues of pain management 289
- Pain relief as a legal right 289
- Pain relief and the WHO 289
- Regulatory issues 289
- Opioids and cannabinoids 289
- DEA and use of opioids for pain relief in terminal care 289
- FDA and COX-2 inhibitors 290
- Legal issues of COX-2 inhibitors 291
- Regulatory issues of opioid safety 291
- Opioid misuse and regulatory agencies 291
- FDA measures for safety of opioid use 291
- Misuse of fentanyl 292
8. Pain Markets 293
- Introduction 293
- Epidemiological basis of pain markets 293
- Cancer 294
- Neuropathic pain 294
- Trigeminal neuralgia 294
- Arthritis 294
- Backache 294
- Migraine 295
- Multiple sclerosis 295
- Irritable bowel syndrome 295
- Chronic pelvic pain 295
- Chronic pain due to traumatic brain injury 295
- Postsurgical pain 296
- Economics of pain 296
- Pain as a driver of healthcare costs 296
- Disability and financial loss through pain 297
- Pain markets based on painful conditions 297
- The cancer pain market 297
- The arthritis pain market 298
- Postsurgical pain market 298
- The backache market 298
- The headache market 299
- Neuropathic pain market 299
- Fibromyalgia market 300
- Pain markets based on drugs 300
- Opioids 300
- Nonsteroidal antiinflammatory drugs 301
- Transdermal pain therapeutics 301
- Anesthesia 301
- Antiepileptic drugs as analgesics 302
- Other drugs 302
- Hospital vs retail share of pain market 302
- Hospital versus retail opioid market 302
- Devices for pain 302
- Pain markets according to geographical areas 303
- Cost effectiveness of various approaches 303
- Unfulfilled R&D needs in pain therapy 304
- Under treatment of pain 304
- Unfulfilled needs in drug development for chronic pain 304
- Strategies for developing pain markets 305
- Finding alternatives to intrathecal administration for chronic pain 305
- Development of other applications of analgesic drugs 305
- Partnership of patients, pharmacists and companies 306
- Factors that may influence future pain markets 306
- Drivers of pain markets 306
- Public surveys as indicators of impact of pain on people 307
- Effect of regulatory reviews on markets for pain products 307
- Novel versus older therapies for pain 308
9. Future of Pain Therapeutics 309
- Introduction 309
- Advances in the understanding of pain 309
- Pathogenesis of chronic pain 309
- Role of glia in neuropathic pain 309
- Molecular and neurobiological techniques 310
- Improved understanding of cancer pain 311
- Advances in drug discovery and development for pain 311
- Novel targets for drug discovery for pain 311
- PTH2 receptor 311
- Modulators of endogenous cannabinoids 312
- Application of new technologies to pain therapeutics 312
- Application of nanobiotechnology to pain therapeutics 313
- Technologies for the manufacture of analgesics 314
- Future trends and needs in pain management 314
- Pain management in future healthcare systems 315
- Systems biology approach to pain 315
- Personalized pain management 316
- Pharmacogenomics and pharmacogenetics of pain 317
- Genetic mutations associated with reduced response to analgesics 318
- Genetic mutations with loss of pain 318
- Mechanism-specific management of pain 319
- Preoperative testing to tailor postoperative analgesic requirements 319
- Strategies for improving pain management 319
10. Companies Involved in Pain Therapeutics 321
- Introduction 321
- Profiles of companies 321
- Collaborations 490
11. References 495
Tables
- Table 1-1: Landmarks in the history of pain therapeutics 20
- Table 1-2: Classification of pain 22
- Table 1-3: Classification of neuropathic pain 24
- Table 1-4: Classification of chronic cancer pain according to cause 25
- Table 1-5: Percentage of patients with pain according to the type of
cancer 26
- 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 61
- Table 2-2: Chronic pain as a manifestation of other diseases 62
- Table 2-3: Recommendations for assessing patient satisfaction with pain
management 67
- Table 3-1: Classification of some currently used pain medications
according to mechanism 74
- Table 3-2: Drugs used for the treatment of pain 74
- Table 3-3: Selective COX-2 inhibitors in clinical use for pain 76
- Table 3-4: Antiepileptic drugs with analgesic effect 90
- Table 3-5: Companies with products to deter abuse of opioids 101
- Table 4-1: Non-pharmacological approaches to management of pain 107
- Table 4-2: Companies involved in neuromodulation therapy for pain 113
- Table 4-3: Reasons for the inadequate management of acute pain 115
- Table 4-4: Causes of chronic backache 131
- Table 4-5: Management of chronic pelvic pain 134
- Table 4-6: Management of pain in cancer 135
- Table 4-7: Definitions of tolerance, physiological dependence, withdrawal
and addiction 141
- Table 4-8: A simplified classification of headache 141
- Table 4-9: Various methods for the management of migraine 142
- Table 4-10: Management of neuropathic pain based on mechanism and
diagnosis 152
- Table 4-11: Management of central neuropathic pain 155
- Table 4-12: Current management of peripheral diabetic neuropathy 158
- Table 4-13: Treatment strategies for postherpetic neuralgia 160
- Table 4-14: Management of complex regional pain syndrome 162
- Table 4-15: Methods of treating phantom limb pain 164
- Table 4-16: Treatment of chronic unexplained pain due to central
sensitization 170
- Table 4-17: Anti-itching therapies 171
- Table 4-18: Suggested improvements in the management of pain 181
- Table 5-1: A classification of drug delivery methods used in management of
pain 183
- Table 5-2: Selected marketed non-injection drug delivery systems for pain
187
- Table 5-3: Spinal administration of drugs for pain 202
- Table 5-4: Selected drug delivery systems for pain in clinical development
208
- Table 6-1: Classification of drugs in development for pain 211
- Table 6-2: Preclinical studies on cannabinoid (CB2) receptor agonists as
analgesics 216
- Table 6-3: Cannabinoid receptor agonists in clinical development as
analgesics 217
- Table 6-4: NO-related therapies for pain 234
- Table 6-5: Major opioids receptors and their ligands 237
- Table 6-6: Strategies to counteract pain at various levels at periphery
and in the CNS 243
- Table 6-7: Types of TRPV1 antagonists 244
- Table 6-8: TRPV1 antagonists in clinical trials 244
- Table 6-9: Experimental gene therapy approaches for relief of pain 252
- Table 6-10: Selected preclinical approaches to pain therapy 260
- Table 6-11: Selected preclinical drugs for neuropathic pain 262
- Table 6-12: Selected clinical trials of miscellaneous drugs for pain
268
- Table 6-13: Selected clinical trials of drugs for postsurgical pain 271
- Table 6-14: COX-2 inhibitors in clinical development 273
- Table 6-15: Disease modifying drugs for arthritis in clinical trials
274
- Table 6-16: Clinical trials of drugs for neuropathic pain 275
- Table 6-17: Selected drugs in clinical development for migraine 285
- Table 6-18: Therapeutic targets for treating visceral pain 288
- Table 8-1: Market values for various painful conditions 2011-2021 297
- Table 8-2: Changes in market shares of drugs for neuropathic pain
2011-2021 299
- Table 8-3: Markets for pain according to therapies 2011-2021 300
- Table 8-4: Distribution of value of pain therapeutics in major markets
2011-2021 303
- Table 8-5: Distribution of value of opioids in major pain markets
2011-2021 303
- Table 8-6: Distribution of value of NSAIDs in major pain markets 2011-2021
303
- Table 8-7: Strategies for developing pain markets 305
- Table 9-1: P450 isoforms in the metabolism of drugs used in the management
of pain 317
- Table 10-1: Product pipeline of Adolor Corporation 327
- Table 10-2: Selected collaborations in the area of pain management 490
Figures
- Figure 1-1: Afferent pain pathways 28
- Figure 1-2: Evolution of the gate control theory 30
- Figure 1-3: The body self-neurometric 31
- Figure 1-4: Various ligands and receptors on the peripheral terminals of
nociceptive nerve fibers 48
- Figure 1-5: Prostaglandin biosynthesis pathway 52
- Figure 2-1: Biopsychosocial factors that interact and modulate the
experience of pain 63
- Figure 2-2: Pain intensity scales 64
- Figure 4-1: The WHO step ladder for pain 136
- Figure 4-2: An algorithm for the acute management of migraine 144
- Figure 4-3: Neuroimmune activation events leading to sensitization of CNS
151
- Figure 4-4: An algorithm for the management of peripheral neuropathic pain
163
- Figure 4-5: Algorithm for management of patients with chronic pain and
depression 168
- Figure 5-1: Powder Injection Systems 194
- Figure 6-1: Attributes of the ideal analgesic 212
- Figure 6-2: Nerve targeting drug delivery system for gene therapy of pain
258
- Figure 8-1: Unfulfilled needs in the treatment for chronic pain 304
- Figure 9-1: Impact of new technologies on pain therapeutics 313
- Figure 9-2: A scheme of personalized management of pain 316
