Pain Therapeutics - Drugs, Markets and Companies
NEW YORK, Feb. 1, 2012 /PRNewswire/ -- Reportlinker.com announces that a new market research report is available in its catalogue:
Pain Therapeutics - Drugs, Markets and Companies
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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 CONTENTS1. 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
Modulation of pain by pictures associated with social contacts 33
Modulation of pain by emotions 33
Role of the sympathetic nervous system in pain 34
Visceral pain 34
Pathomechanism of visceral pain 34
Pathomechanism of neuropathic pain 35
Role of intact nerve fibers in neuropathic pain 35
Chemokines as mediators of neuropathic pain 35
Chemotherapy-induced neuropathic pain 36
CNS innate immunity and neuropathic pain 36
Cytokines as mediators of neuropathic pain 36
Free radicals in generation of neuropathic pain 36
Genetic basis of neuropathic pain 37
Gene expression changes in neuropathic pain 37
Glial activation and neuropathic pain 38
Immune cell-derived opioids and neuropathic pain 38
Spinal leptin and neuropathic pain 38
Tetrahydrobiopterin regulates neuropathic pain sensitivity 39
Pathomechanism of migraine 39
Role of the immune system in pain 40
Pain and itch 40
Pathomechanism of itch 40
Clinical aspects of itch 41
Molecular pathophysiology of pain 41
Role of ion channels in pain 41
Acid-sensing ion channels 42
Calcium channels in pain 42
P2X3 ion channels 43
Potassium ion channels 43
Sodium ion channels in pain 44
TRP ion channels in pain 45
Genetic basis of pain 45
Study of genes in pain 46
Pain as a channelopathy 47
Pain in the brain 47
Neuropathic pain-induced morphological changes in the brain 48
Change from acute to chronic pain 48
Descending facilitatory modulation of pain 48
Development of chronic pain following severe accidental injury 49
Pain and transcriptional repressor DREAM 49
Role of neuronal plasticity in pain 49
Neurochemistry of pain 50
Molecular elements of pain in the peripheral nervous system 50
Molecular elements of pain in the central nervous system 51
Opioid receptors 51
Role of AMPA receptors in chronic pain 52
Kinins 52
Serotonin 52
Substance P 53
Excitatory amino acids 53
Role of nitric oxide in pain 53
Prostaglandins 54
Endocannabinoids 55
Protein kinase C 55
Adenosine and adenosine receptors 55
Vitamin D and pain 55
Vanilloid receptor 56
TRPA1 and TRPV1 receptors 56
Endothelin-B receptors 57
Nerve growth factor and pain 57
Adrenomedullin as a pain-related peptide 58
Biomarkers of pain 58
Biomarkers of visceral pain 58
2. Assessment of Pain and Analgesics 61
Introduction 61
Animal models of pain 61
An overview 61
Selection of animal species as models for pain 61
Types of noxious stimuli 62
Animal models of neuropathic pain 62
Animal models of arthritis 62
Animal models of peripheral neuropathy 63
Limitations of current pain models 63
Biogenic animal model of chronic pain 64
Ethical issues concerning animal pain models 64
Medical evaluation of pain 65
Chronic pain as a manifestation of various diseases 65
Assessment of pain patients 65
Medical examination 65
Measurement of pain 66
Quantitative sensory testing 67
Pain measurement tools for neonates and children 68
Quantitative sensory testing 68
Psychological assessment of pain 69
Brain imaging in pain 69
PET for study of pain 69
PET correlated with fMRI and evoked potentials 70
Patient outcomes and quality of life during treatment for chronic pain 70
Collection and analysis of data on pain patients 71
Evaluation of analgesics in humans 71
Early phase clinical trials of analgesics in humans 71
Design of clinical trials for pain 72
Assessment of neuropathic pain 73
Transdermal electrical stimulation for study of chronic pain 73
Placebo effect in pain 74
Role of electronic pain recording in determination of the placebo effect 74
Outcome measures for chronic pain trials 75
Pain, pain therapies and cognitive function 75
3. Pharmacotherapy of Pain 77
Introduction 77
Mechanism of action of currently used pain medications 77
Non-steroidal antiinflammatory drugs 78
COX-2 inhibitors 78
Celecoxib 79
Metamizole 80
Nimesulide 80
Rofecoxib 80
Valdecoxib 81
Lumiracoxib 81
Side effects of COX inhibitors 82
Innovative COX-2 inhibitors in development 83
Acetaminophen 84
Antioxidants as analgesics 84
Opiates and opioids 85
Innovations in opioid therapy 85
Oral transmucosal fentanyl 86
Use of opioids for chronic non-cancer pain 86
Opioid receptor modulation for visceral pain 86
Opiorphin 87
N-methyl-D-aspartate receptor antagonists 87
Ketamine 87
CNS 5161 88
Triptans for treatment of non-migrainous pain 88
Capsaicin 88
NGX-4010 89
Local anesthetics 89
Topical application 89
Nerve blocks 89
Injection of local anesthetics for analgesia 90
Ultrasound-guided nerve blocks 90
Topical salicylates for the treatment of pain 90
Topical rubefacients for acute and chronic pain in adults 90
Adjunctive analgesics 91
Antidepressants 91
Mechanism of analgesic action of antidepressants 92
Antiepileptic drugs 93
Mechanism of action of antiepileptic drugs in neuropathic pain 93
Carbamazepine 94
Gabapentin 94
Lamotrigine 95
Phenytoin 95
Pregabalin 96
Topiramate 97
Valproic acid 97
Other antiepileptic drugs 97
Clonidine 97
Baclofen 98
Corticosteroids 98
Calcitonin 99
Bisphosphonates 99
Botulinum toxins 99
Analgesic effect of botulinum toxin A 100
Engineered botulinum toxin 100
Analgesics from traditional medical systems 100
Herbs and other plants 101
Analgesics derived from cobra toxin 102
Adverse effects of analgesics 102
Gastrointestinal adverse effects of NSAIDs 102
Measures to reduce gastrointestinal adverse effects of NSAIDs 102
Cardiovascular adverse effects of COX-2 inhibitors 102
Adverse effects of opioids 103
Risk of addiction and development of tolerance 103
Companies developing products to deter abuse of opioids 103
Remoxy versus Oxycontin 104
Hyperalgesia associated with opioids 104
Respiratory depression 105
Opioid-associated constipation 105
Narcotic bowel syndrome 105
Adverse effects of use of opioids in non-malignant pain 105
Approaches to reduce adverse effects of opioids 106
PEGylated naloxol 106
Innovative approaches to modify opioid pharmacology 106
Regulatory aspects of opioid abuse, overdose and death 106
Adverse effects of miscellaneous non-narcotic analgesics 107
Adverse effects of immunosuppressants used for relief of pain 107
Adverse effects of acetaminophen 108
4. Management of Pain 109
Introduction 109
Sites for pain management 109
Self-medication at home 109
Physicians' offices 109
Major hospitals 109
Pain centers 110
Non-pharmacological approaches to pain 110
Alternative medicine 110
Acupuncture 111
Aromatherapy 111
Self-Controlled Energo Neuro Adaptive Regulation 112
Behavioral therapy 112
Cognition and pain 112
Control over brain activation and pain by using functional MRI 112
Thermal-grill illusion 113
Virtual reality therapy 113
Local application of heat 113
Transcutaneous nerve stimulation 114
Transcranial magnetic stimulation 114
Neurosurgery for pain relief 114
Ablative procedures on the nervous system 115
Procedures on peripheral, spinal and cranial nerves 115
Vagal nerve stimulation for control of pain 115
Neuromodulation 115
Spinal cord stimulation 116
Brain stimulation 117
Implantation of drug delivery devices 117
Management of special types of pain 117
Acute pain 117
Management of acute renal colic: NSAIDS vs. opioids 117
Combination of opioids and NSAIDs for acute pain 118
Reasons for inadequate management of acute pain 118
Perioperative pain management 118
Devices for delivery of analgesics in the postoperative period 119
Drug combination for perioperative pain 120
Gabapentin for reduction of postoperative pain 120
Ketamine for perioperative pain 120
Opioids for perioperative pain 121
Perioperative pain in neurosurgery 121
Prolonged duration local anesthesia 121
Concluding remarks on the management of postoperative pain 122
Pain in the intensive care unit 122
Pain associated with sports and exercise 123
Pain associated with trauma 123
Chronic abdominal pain 124
Functional somatic syndromes 124
Fibromyalgia syndrome 124
Pathomechanism of FMS 125
Management of FMS 125
New developments in pharmacotherapy of FMS 126
Erythromelalgia 127
Irritable bowel syndrome 127
Opioids for IBS 128
Tricyclic antidepressants for IBS 128
Serotonin-modulating drugs for IBS 129
Musculoskeletal pain 129
Myofascial pain syndrome 129
Osteoarthritis 130
Pathomechanism of osteoarthritis 130
Pain aggravates osteoarthritis by crosstalk between CNS and the joint 131
Management of osteoarthritis 131
Rheumatoid arthritis 132
Management of pain in rheumatoid arthritis 133
Disease modifying therapies in rheumatoid arthritis 133
Resurgence of interest in gold-based treatments for RA 134
Backache 134
Use of analgesics for management of back pain 135
Miscellaneous medical therapies for backache and sciatica 136
Neck pain 136
Chronic pelvic pain 137
Prostatitis 137
Cancer pain 137
Opioid treatment of cancer pain 138
Breakthrough and opioid-insensitive pains 139
Morphine-induced enhancement of cancer growth and its prevention 139
Methods of delivery of opioids for cancer pain 140
Implantation of drug delivery devices 140
Management of bone pain in cancer 141
Use of non-opioid analgesics for cancer pain 141
Adjuvant drugs for cancer pain 142
Radiation therapy 142
Alternative non-pharmacological methods 142
Anesthetic techniques 142
Surgical methods of cancer pain relief 142
Conclusions regarding management of cancer pain 143
Chronic non-malignant pain 143
Headache 144
Migraine 144
Management of acute migraine 145
Neurostimulation for migraine 149
Transcranial magnetic stimulation for migraine 150
Migraine prophylaxis 150
Cluster headache 151
Paroxysmal hemicrania 151
Tension headache 151
Chronic daily headache 152
Trigeminal neuralgia 152
Dental pain 153
Neuropathic pain 153
Pathogenesis of neuropathic pain 153
Chronobiology of neuropathic pain as guide to therapy 154
Management of neuropathic pain based on mechanism 155
Guidelines for the management of neuropathic pain 155
Pharmacotherapy of neuropathic pain 155
Evidence-based management of neuropathic pain 158
Management of central neuropathic pain 158
Neurosurgical approaches to central neuropathic pain 158
Management of neuropathic pain in syringomyelia 159
Neuropathic pain associated with spinal cord injury 159
Peripheral neuropathic pain 160
Management of postsurgical peripheral neuropathic pain 160
Management of chemotherapy-induced pain 160
Morton's neuroma 161
Management of peripheral diabetic neuropathy 161
Postherpetic neuralgia 163
Complex regional pain syndrome 165
An algorithm for the management of peripheral neuropathic pain 166
Phantom limb pain 167
Pathomechanism of phantom limb pain 167
Management of phantom limb pain 167
Pain and depression 169
Neurochemical link between pain and depression 170
Management of chronic pain and depression 170
Miscellaneous painful conditions 171
Burning mouth syndrome 171
Chronic unstable angina 172
Mastalgia 172
Ophthalmic pain 172
Pain in Parkinson's disease 173
Management of chronic unexplained pain 173
Management of itching 173
Topical applications for itching 174
Systemic therapies for itching 175
Non-pharmacological therapies for itch 176
Management of pain in special population groups 176
Racial and ethnic differences in pain management 176
Pain in neonates 176
Management of pain in children 177
Management of pain in the elderly 177
Management of pain in women 179
Reasons for increased pain perception in women 179
Chronic pelvic pain in women 179
Gender differences in response to analgesics 179
Considerations for pain management in women 180
Management of pain in neurologically handicapped persons 180
Management of pain in the cognitively impaired elderly people 181
Management of pain in brain-damaged minimally conscious patients 181
Management of pain in the terminally ill 182
Deficiencies in the management of pain 182
Negative physician attitudes in pain management 183
Suggestions for improvement of pain management by healthcare providers 183
Pain as the fifth vital sign 184
Management of neuropathic pain in patients refractory to first line treatment 184
Multidisciplinary approaches to pain management 184
5. Drug Delivery for Pain 187
Introduction 187
Intra-articular injection for relief of joint pain 188
Controlled release drug delivery for pain 188
Accelerating the effect of subcutaneous morphine 188
Controlled drug delivery at site of pain 188
Oral extended release opioids 189
Extended release oral morphine 189
Controlled release oxycodone 190
Extended release oxymorphone 190
Oral extended release tramadol 190
Extended release gabapentin 191
Use of nanotechnology for drug delivery for pain 191
Non-injection methods of delivery of analgesics 191
Topical applications for pain 192
Topical local anesthetics 192
Topical NSAIDs 192
Topical and transdermal diclofenac 193
Topical application for postoperative pain 193
Needle-free drug delivery for pain 194
Glide SDI® solid dose injector 194
SUMAVEL™ DosePro™ needle-less injection 194
Transdermal drug delivery for pain 194
Relief of pain associated with minor medical procedures 194
Transdermal fentanyl 195
Transdermal ketoprofen 196
Transdermal nitroglycerine as an adjuvant to opioids 197
Transdermal buprenorphine 197
Transdermal trans-capsaicin 197
Powder Injection Systems 198
Intranasal delivery of analgesics 198
Intranasal morphine 199
Intranasal morphine derivatives 199
Intranasal fentanyl 200
Intranasal buprenorphine 200
Intranasal ketamine 200
Intranasal ketorolac 201
Nasal formulations for migraine 201
Oral spray formulations for migraine 201
Delivery of analgesics by inhalation 202
Buccal transmucosal and sublingual delivery of analgesics 203
Application for cancer pain 203
Application for non-cancer pain 203
Pumps for drug delivery in pain 204
Patient controlled analgesia 204
Postoperative pain pumps 204
Chronogesic (sufentanil) Pain Therapy System 205
Spinal pumps for delivery of analgesics 206
Spinal delivery of analgesics 206
Epidural administration of analgesics 207
Epidural dexamethasone 207
Epidural etanercept 208
Epidural morphine 208
Intrathecal administration of analgesics 208
Intrathecal CGX1160 208
Intrathecal fadolmidine 208
Intrathecal lidocaine 209
Intrathecal neostigmine 209
Intrathecal non-NMDA antagonists 209
Intrathecal prostaglandin antagonists 209
Intrathecal resiniferatoxin 210
Intrathecal ziconotide 210
Concluding remarks on intrathecal delivery of analgesic agents 211
Intracerebroventricular morphine for pain 211
Development of drug delivery systems for pain therapy 211
Delivery of analgesics to the CNS across the blood brain barrier 212
Drug delivery systems in clinical trials 212
6. Drug Development for Pain 215
Introduction 215
Drugs in development for pain 215
Current research goals 216
The ideal analgesic 216
Pain R & D goals in the pharmaceutical industry 216
Drug targets in the spinal cord 217
Drug targets in the brain 217
Molecular targets for analgesic drugs 217
Activation of P2X7 receptors 217
Adenosine receptor agonists 218
Alfa2-adrenergic receptor agonists 218
Anti-NGF strategies 218
Bradykinin antagonists 219
Cannabinoids 219
Cannabinoid receptor agonists 220
Cannabidiol 221
Cannabinor 222
Nabilone 222
Capsaicin and VR1 receptor-based analgesics 223
Vanilloid (capsaicin) receptor antagonists 223
VR1 receptor agonists 223
CCR2 receptor blockade 224
Cholecystokinin antagonists 224
Cholinergic receptor agonists 224
Conotoxins as analgesics 225
Corticotropin-releasing factor 226
FAAH inhibitors 226
PF-3845 227
URB597 227
Free radical scavengers as analgesics 227
Superoxide dismutase mimetics 228
GABA analogues 228
Subtype-selective GABAergic drugs 228
Glial cell line-derived neurotrophic factor 229
Glutamate receptor antagonists 229
NMDA receptor modulation for neuropathic pain 229
Alternatives to direct blocking of NMDA receptors 230
Glycine antagonists 230
Metabotropic glutamate receptors 230
Histogranin-like compounds for the management of pain 231
Ion channels as targets for analgesic drugs 231
Acid-sensing ion channels as drug target 231
Calcium channel blockers 232
P2X ion channel receptor antagonists 232
Sodium channel modulation 233
Mas-related GPCR agonists 233
Microsomal prostaglandin E synthase inhibitors 234
NAALADase inhibitors 235
Nerve growth factor antagonists 235
Newer COX inhibitors 235
COX-3 inhibitors 236
Dual cyclooxygenase/lipoxygenase inhibitors 236
Neuropeptide receptor antagonists for improving the efficacy of opioids 236
Nicotinic acetylcholine receptors 236
Mode of action of nACh/neural nicotinic receptor agonists 237
Potential of central nACh/neural nicotinic receptor agonists 237
Nitric oxide-based analgesics 238
Nitric oxide-releasing NSAIDs 238
Pharmacology of NO-SAIDs 239
COX-inhibiting nitric oxide donors 239
NO-donating structures to extend life cycle of existing analgesics 240
Nitric oxide mimetics 240
Neuronal nitric oxide synthase inhibitors 240
Norepinephrine transporter inhibition 240
Opioid peptide receptors ligands 241
Opioids with unique receptor characteristics 242
Buprenorphine 242
Nociceptin 242
Tapentadol 243
Opioid analgesics acting outside the CNS 243
Opioid analgesics acting at peripheral receptors 243
Peripherally acting mu-opioid receptor agonists 244
Targeting of opioid peptide-containing immune cells 244
Advantages of peripherally selective opioid drugs 244
Resolvins 245
Somatostatin analogs 245
Substance P and neurokinin receptor antagonists 245
Substance P-Saporin 246
Targeting prostanoid synthesis 246
Tetrodotoxin based analgesics 247
TRPV1 antagonists 247
TRPV1 antagonists in clinical trials 248
TRPV1-mediated entry of sodium channel blocker QX-314 249
Tumor necrosis factor-? antagonists 249
Cell and gene therapies for pain 250
Cell therapy 250
Implantation of chromaffin cells 250
Role of stem cells in management of pain 251
Implantation of astrocytes secreting enkephalin 251
Cells for delivery of antinociceptive molecules 251
Implantation of genetically engineered cells 252
Cell therapy for low back pain 252
Cell therapy for knee pain due to degenerative disorders 253
Cell therapy for peripheral neuropathic pain 253
Concluding remarks on cell therapy for pain 253
Gene therapy 254
Rationale of gene therapy for pain 254
Vectors for gene therapy of pain 255
Methods of gene delivery for pain 255
Vectors for endogenous analgesic production in cranial neuralgias 256
Gene delivery by intrathecal route 256
Gene transfer to the dorsal nerve roots 257
Gene therapy of peripheral neuropathy 258
Gene transfer by injections into the brain substance 258
Zinc finger DNA-binding protein therapeutic for chronic pain 259
Gene therapy for producing enkephalin to block pain signals 259
Targeting nuclear factor-?B 260
Gene therapy targeted to neuroimmune component of chronic pain 260
Antisense therapy for pain 260
RNAi-based approaches for pain therapy 261
Potential applications of gene therapy for management of pain 262
Concluding remarks about gene therapy for pain 262
Preclinical development of pain drugs 263
NGF-blocking antibody 264
Prostatic acid phosphatase as a novel analgesic 264
Preclinical development of drugs for neuropathic pain 264
5-HT receptor agonists 265
A-803467 266
AM1241 266
Artemin/Neuroblastin 266
Capsazepine 267
Central nACh receptor agonists 267
CGP 35024 267
Drugs that suppress glial activation 268
Erythropoietin 268
Gene therapy for neuropathic pain 268
NCX 8001 269
NR2B subtype NMDA receptor ligands 269
NW-1029 270
R116301 270
Targeting tumor necrosis factor 270
Future targets for osteoarthritic pain 270
Pain drugs in clinical trials 271
Clinical trials of miscellaneous drugs for pain 271
Alvimopan 273
Asimadoline 273
EN3202 274
Oxytrex 274
Drugs in clinical trials for postsurgical pain 274
Bicifadine 275
DepoMorphine 276
Cox-2 inhibitors in clinical trials 276
Clinical trials of disease modifying therapies for arthritis
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