Pain Therapeutics

Drugs, Markets & Companies

Prof. K. K. Jain MD, FRACS, FFPM Jain PharmaBiotech Basel, Switzerland

September 2021

A Jain PharmaBiotech Report

AUTHOR'S BIOGRAPHY

Professor K. K. Jain is a neurologist/neurosurgeon with specialist qualifications including Fellowships of the Royal Colleges of Surgeons in Australia and Canada. He has trained, practiced and held academic positions in several countries including Switzerland, India, Iran, Germany Canada and USA. After retirement from neurosurgery, Prof. Jain remains a consultant in neurology. He is also working in the biotechnology/biopharmaceuticals industry and is a Fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians of UK. Currently is the CEO at Jain PharmaBiotech.

Prof. Jain’s 492 publications include 35 books (6 as editor+ 29 as author) and 50 special reports, which have covered important areas in biotechnology, gene therapy and biopharmaceuticals, biomarkers: proteomics, molecular diagnostics, nanobiotechnology, and personalized medicine. Contributions to MedLink, an accredited continuing education program for neurologists, include 172 articles out of a total of 1250 articles by 450 authors. These articles are updated on a yearly basis. Prof. Jain’s earlier books were the first in the areas covered: “Handbook of Laser Neurosurgery” (Charles C. Thomas, Springfield, Ill, 1983) and “Textbook of Hyperbaric Medicine” (1st ed in 1990 and 6th ed by Springer, 2017). His “Textbook of Gene Therapy" was translated into Chinese in 2000. Recent books include “Handbook of Nanomedicine” (Springer 2008, Chinese edition by Peking University Press 2011, 3rd ed 2017), “Textbook of Personalized Medicine” (Springer 2009; Japanese ed 2012; 2nd ed Springer 2015, 3rd ed 2021), "Handbook of Biomarkers" (Springer 2010; Chinese ed, Chemical Industry Press 2016, 2nd ed 2017), “Drug-induced Neurological Disorders”, 4th ed (Springer 2021), "Handbook of Neuroprotection” (Springer 2011, 2nd ed 2019), “Applications of Biotechnology in Cardiovascular Therapeutics” (Springer 2011), “Applications of Biotechnology in Neurology” (Springer 2013), and “Applications of Biotechnology in Oncology” (Springer 2014). He has also edited 3 editions of “Drug Delivery System” (Springer 2008, 20012 and 2020) and “Applied Neurogenomics” (Springer 2015). Lectures on personalized medicine given at Kazakh National Medical University, Kazakhstan were translated into Russian and published as a book “Essentials of Personalized Medicine” (LITERRA Publishing House, Moscow, 2019). Currently, he is writing “The Handbook of Alzheimer Disease” to be published by Springer in 2022.

ABOUT THIS REPORT

The pain report is an update with inclusion of commercial information in an earlier publication titled "Pain Therapeutics: A strategic re-evaluation" published by Reuter's Business Insight/Datamonitor UK in 2000. Other reports written by Prof. Jain in the past have been published by PJB Publications, D & MD, Informa, and Decision Resources Inc. This is one of the in-house publications of Jain PharmaBiotech that are constantly updated.

Jain PharmaBiotech Bläsiring 7 CH-4057 Basel Switzerland

Tel & Fax: +4161-6924461 Email: [email protected] Web site: http://pharmabiotech.ch/

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

- 2 - TABLE OF CONTENTS

0. Executive Summary ...... 18

1. Basic Aspects of Pain ...... 20 Introduction ...... 20 Historical aspects of pain ...... 20 Pain definitions ...... 22 A glossary of terms relevant to pain ...... 23 Pain classification and description ...... 23 Neuropathic pain...... 24 Refractory neuropathic pain ...... 25 Classification of neuropathic pain according to levels ...... 25 Cancer pain ...... 26 Bone pain in cancer ...... 28 Complex regional pain syndrome ...... 28 Mechanisms of pain ...... 29 Pain pathways ...... 29 Pain organ of the skin ...... 31 Role of nociceptors in pain transmission ...... 32 Gate control and neuromatrix theories of pain ...... 32 Pain mediators ...... 33 Modulation of pain by pictures associated with social contacts ...... 34 Modulation of pain by emotions ...... 34 Role of the sympathetic nervous system in pain ...... 34 Pathomechanism of inflammatory pain ...... 34 Pathomechanism of visceral pain ...... 35 Pathomechanism of neuropathic pain ...... 36 Role of intact nerve fibers in neuropathic pain ...... 36 Chemokines as mediators of neuropathic pain ...... 36 Chemotherapy-induced neuropathic pain ...... 36 CNS innate immunity and neuropathic pain ...... 37 Cytokines as mediators of neuropathic pain ...... 37 Free radicals in generation of neuropathic pain ...... 37 GABA deficiency in neuropathic pain ...... 38 Genetic basis of neuropathic pain ...... 38 Gene expression changes in neuropathic pain ...... 38 Glial activation and neuropathic pain ...... 39 Immune cell-derived opioids and neuropathic pain ...... 39 Spinal leptin and neuropathic pain ...... 39 Tetrahydrobiopterin regulates neuropathic pain sensitivity ...... 40 Pathomechanism of migraine ...... 40 Role of the immune system in pain ...... 41 Pain and itch ...... 41 Pathomechanism of itch ...... 41 Clinical aspects of itch ...... 42 Molecular pathophysiology of pain ...... 43 Role of ion channels in pain ...... 43 Acid-sensing ion channels ...... 43 Calcium channels in pain ...... 44 P2X3 ion channels ...... 44 Potassium ion channels ...... 44 Sodium ion channels in pain ...... 45 TRP ion channels in pain ...... 46 Genetic basis of pain ...... 47 Alternative RNA splicing and pain ...... 48 Study of genes in pain ...... 48 Pain as a channelopathy ...... 49 Pain in the brain ...... 49 Effect of chronic pain on opioid receptors in the brain ...... 50 Neuropathic pain-induced morphological changes in the brain ...... 50 Pain and dementia ...... 50 Change from acute to chronic pain ...... 50 Acute versus chronic pain ...... 51 Descending facilitatory modulation of pain ...... 51 Development of chronic pain following severe accidental injury ...... 51 Pain and transcriptional repressor DREAM ...... 52 Role of neuronal plasticity in pain ...... 52 Role of epigenetics in development of chronic pain ...... 53 Role of glial cells in chronic pain pathways ...... 53

- 3 - Concluding remarks on evolution of acute pain into chronic pain ...... 53 Neurochemistry of pain ...... 53 Molecular elements of pain in the peripheral nervous system ...... 54 Molecular elements of pain in the central nervous system ...... 55 Opioid receptors ...... 56 Role of AMPA receptors in chronic pain ...... 56 Kinins ...... 56 Serotonin ...... 57 Substance P ...... 57 Excitatory amino acids ...... 57 Role of nitric oxide in pain ...... 58 Prostaglandins ...... 58 Endocannabinoids ...... 59 Protein kinase C ...... 60 Adenosine and adenosine receptors ...... 60 Vitamin D and pain ...... 60 Vanilloid receptor ...... 60 TRPA1 and TRPV1 receptors ...... 61 Endothelin-B receptors ...... 62 Nerve growth factor and pain ...... 62 Adrenomedullin as a pain-related peptide ...... 63 Biomarkers of pain ...... 63 Biomarkers of visceral pain ...... 63

2. Assessment of Pain and Analgesics ...... 66 Introduction ...... 66 Animal models of pain ...... 66 An overview ...... 66 Selection of animal species as models for pain ...... 66 Types of noxious stimuli ...... 67 Animal models of neuropathic pain ...... 67 Animal models of arthritis ...... 67 Animal models of peripheral neuropathy ...... 68 Limitations of current pain models ...... 68 NeuroDigm GEL Model™ of neuropathic pain ...... 69 Ethical issues concerning animal pain models ...... 69 Medical evaluation of pain ...... 69 Chronic pain as a manifestation of various diseases ...... 69 Assessment of pain patients ...... 70 Medical examination ...... 70 Measurement of pain ...... 71 Quality of pain intensity assessment in clinical research studies ...... 72 Quantitative sensory testing ...... 73 Pain measurement tools for neonates and children ...... 73 Quantitative sensory testing ...... 74 Microneurographic recordings ...... 74 Psychological assessment of pain ...... 75 Testing for in vivo pain processing ...... 75 Brain imaging in pain ...... 75 fMRI for study of pain ...... 75 PET for study of pain ...... 75 PET correlated with fMRI and evoked potentials ...... 76 Patient outcomes and quality of life during treatment for chronic pain ...... 76 Collection and analysis of data on pain patients ...... 77 Evaluation of analgesics in humans ...... 77 Early phase clinical trials of analgesics in humans ...... 77 Design of clinical trials for pain ...... 78 Assessment of neuropathic pain ...... 79 Transdermal electrical stimulation for study of chronic pain ...... 79 Placebo effect in pain ...... 80 Role of electronic pain recording in determination of the placebo effect ...... 80 Outcome measures for chronic pain trials ...... 80 Pain, pain therapies and cognitive function ...... 81

3. Pharmacotherapy of Pain...... 82 Introduction ...... 82 Sites of action of various pain therapies ...... 82 Mechanism of action of currently used pain medications ...... 83 Non-steroidal antiinflammatory drugs ...... 84 COX-2 inhibitors ...... 84 Celecoxib ...... 85

- 4 - Metamizole ...... 86 Nimesulide ...... 86 Rofecoxib ...... 86 Valdecoxib ...... 86 Lumiracoxib ...... 87 Side effects of COX inhibitors ...... 87 Innovative COX-2 inhibitors in development ...... 89 Acetaminophen ...... 89 Antioxidants as analgesics ...... 90 Opiates and opioids ...... 90 Codeine ...... 91 Morphine ...... 92 Morphine vs methadone ...... 92 Tramadol ...... 92 Innovations in opioid therapy ...... 92 Oral transmucosal fentanyl ...... 92 Use of opioids for chronic non-cancer pain ...... 93 Opioid receptor modulation for visceral pain ...... 93 Opiorphin ...... 94 Sufentanil ...... 94 N-methyl-D-aspartate receptor antagonists ...... 94 Ketamine ...... 94 CNS 5161 ...... 95 Triptans for treatment of non-migrainous pain ...... 95 Capsaicin ...... 95 NGX-4010 ...... 96 Local anesthetics ...... 96 Topical application ...... 96 Nerve blocks ...... 96 Injection of local anesthetics for analgesia ...... 97 Ultrasound-guided nerve blocks ...... 97 Topical salicylates for the treatment of pain ...... 97 Topical rubefacients for acute and chronic pain in adults ...... 97 Adjunctive analgesics ...... 98 Antidepressants ...... 98 Mechanism of analgesic action of antidepressants ...... 99 Antiepileptic drugs ...... 100 Mechanism of action of antiepileptic drugs in neuropathic pain...... 101 Carbamazepine ...... 101 Gabapentin ...... 101 Lamotrigine ...... 102 Phenytoin ...... 102 Pregabalin ...... 103 Topiramate ...... 103 Valproic acid ...... 104 Other antiepileptic drugs ...... 104 Clonidine ...... 104 Baclofen ...... 105 Corticosteroids ...... 105 Calcitonin ...... 106 Bisphosphonates ...... 106 Botulinum toxins ...... 106 Analgesic effect of botulinum toxin A ...... 107 Engineered botulinum toxin ...... 107 Analgesics from traditional medical systems ...... 107 Herbs and other plants ...... 108 Analgesics derived from cobra toxin ...... 108

4. Management of Pain ...... 110 Introduction ...... 110 Sites for pain management ...... 110 Self-medication at home ...... 110 Physicians' offices ...... 110 Major hospitals ...... 110 Pain centers ...... 111 Non-pharmacological approaches to pain ...... 111 Alternative medicine ...... 111 Acupuncture ...... 112 Aromatherapy ...... 112 Self-Controlled Energo Neuro Adaptive Regulation ...... 113 Behavioral therapy ...... 113

- 5 - Cognition and pain ...... 113 Control over brain activation and pain by using functional MRI...... 113 Mindfulness meditation for relief of chronic pain ...... 114 Thermal-grill illusion ...... 114 Virtual reality therapy ...... 114 Local application of heat ...... 114 Transcutaneous nerve stimulation ...... 115 Non-invasive brain stimulation techniques for chronic pain...... 115 Transcranial magnetic stimulation ...... 115 Cranial electrotherapy stimulation ...... 116 Neurosurgery for pain relief ...... 116 Ablative procedures on the nervous system ...... 116 Procedures on peripheral, spinal and cranial nerves ...... 116 Vagal nerve stimulation for control of pain ...... 117 Neuromodulation ...... 117 Spinal cord stimulation ...... 118 Brain stimulation...... 119 Implantation of drug delivery devices ...... 120 Management of special types of pain ...... 120 Acute pain ...... 120 Management of acute renal colic: NSAIDS vs. opioids ...... 120 Combination of opioids and NSAIDs for acute pain ...... 120 Reasons for inadequate management of acute pain ...... 121 Perioperative pain management ...... 121 Devices for delivery of analgesics in the postoperative period ...... 122 Drug combination for perioperative pain ...... 123 Gabapentin for reduction of postoperative pain ...... 123 Ketamine for perioperative pain ...... 123 Opioids for perioperative pain ...... 123 Perioperative pain in neurosurgery ...... 124 Prolonged duration local anesthesia ...... 125 Concluding remarks on the management of postoperative pain ...... 125 Pain in the intensive care unit ...... 125 Pain associated with sports and exercise ...... 126 Pain associated with trauma ...... 126 Chronic pain and sleep ...... 127 Chronic abdominal pain ...... 127 Functional somatic syndromes ...... 127 Fibromyalgia syndrome ...... 128 Pathomechanism of FMS ...... 128 Management of FMS ...... 129 Non-pharmacological therapies for FMS ...... 129 Pharmacotherapy of FMS ...... 129 Concluding remarks on management of FMS ...... 131 Erythromelalgia ...... 131 Irritable bowel syndrome ...... 132 Opioids for IBS ...... 132 Pregabalin for IBS ...... 133 Tricyclic antidepressants for IBS ...... 133 Serotonin-modulating drugs for IBS ...... 133 Musculoskeletal pain ...... 133 Myofascial pain syndrome ...... 134 Non-pharmacological methods of treatment of MPS ...... 134 Pharmacotherapy of MPS ...... 134 Osteoarthritis ...... 135 Pain aggravates osteoarthritis by crosstalk between CNS and the joint ...... 136 Management of osteoarthritis ...... 137 Rheumatoid arthritis ...... 138 Management of pain in rheumatoid arthritis ...... 138 Disease modifying therapies in rheumatoid arthritis ...... 138 Resurgence of interest in gold-based treatments for RA ...... 140 Backache and sciatica ...... 140 Lumbar disc disease and sciatica ...... 141 Clinical trials of backache with sciatica ...... 142 Management of back pain with analgesics ...... 142 Miscellaneous medical therapies for backache and sciatica ...... 143 Neck pain...... 143 Chronic pelvic pain ...... 144 Prostatitis ...... 144 Cancer pain ...... 145 Adjuvant drugs for cancer pain ...... 145

- 6 - Alternative non-pharmacological methods ...... 146 Anesthetic techniques ...... 146 Management of bone pain in cancer ...... 146 Non-opioid analgesics for cancer pain ...... 146 Opioid treatment of cancer pain ...... 146 Opioid breakthrough pains ...... 148 Opioid-induced enhancement of cancer growth and its prevention ...... 148 Opioids delivery methods for cancer pain ...... 148 Opioid administration through implanted drug delivery devices ...... 149 Radiation therapy ...... 150 Surgical methods of cancer pain relief ...... 150 Conclusions regarding management of cancer pain ...... 150 Chronic non-malignant pain ...... 151 Headache ...... 151 Cluster headache ...... 152 Chronic daily headache ...... 152 Indomethacin-responsive headache ...... 153 Occipital neuralgia ...... 153 Paroxysmal hemicrania ...... 154 Post-traumatic headache ...... 154 Tension headache ...... 154 Migraine ...... 155 Management of acute migraine ...... 155 Chronic migraine...... 159 Pediatric migraine ...... 160 Status migrainosus ...... 161 Migraine prophylaxis ...... 162 Non-pharmacological approaches to migraine ...... 162 Trigeminal neuralgia ...... 164 Dental pain ...... 165 Neuropathic pain...... 165 Pathogenesis of neuropathic pain ...... 165 Chronobiology of neuropathic pain as guide to therapy ...... 166 Management of neuropathic pain based on mechanism ...... 166 Guidelines for the management of neuropathic pain ...... 167 Pharmacotherapy of neuropathic pain ...... 167 Evidence-based management of neuropathic pain ...... 169 Management of central neuropathic pain ...... 170 Neurosurgical approaches to central neuropathic pain...... 170 Management of neuropathic pain in syringomyelia ...... 171 Neuropathic pain associated with spinal cord injury ...... 171 Management of peripheral neuropathic pain ...... 171 Truncal neuropathic pain ...... 172 Management of postsurgical peripheral neuropathic pain ...... 172 Management of chemotherapy-induced pain ...... 172 Morton’s neuroma ...... 173 Management of peripheral diabetic neuropathy ...... 173 Postherpetic neuralgia ...... 175 Treatment of complex regional pain syndrome ...... 177 An algorithm for the management of peripheral neuropathic pain...... 178 Phantom limb pain ...... 178 Pathomechanism of phantom limb pain ...... 179 Management of phantom limb pain ...... 179 Painful neuromas following amputation ...... 181 Pain and depression ...... 181 Neurochemical link between pain and depression ...... 182 Management of chronic pain and depression ...... 183 Miscellaneous painful conditions ...... 183 Burning mouth syndrome ...... 183 Chronic unstable angina ...... 184 Mastalgia ...... 184 Ophthalmic pain...... 184 Pain in Parkinson's disease ...... 185 Pain in sickle cell disease ...... 185 Management of chronic unexplained pain ...... 186 Management of itching ...... 186 Topical applications for itching ...... 187 Systemic therapies for itching ...... 188 Non-pharmacological therapies for itch ...... 188 Management of pain in special population groups ...... 188 Racial and ethnic differences in pain management ...... 188

- 7 - Pain in neonates ...... 189 Management of pain in children ...... 189 Misuse of codeine in children ...... 191 Management of pain in the elderly ...... 191 Management of pain in women ...... 192 Reasons for increased pain perception in women ...... 192 Chronic pelvic pain in women ...... 193 Gender differences in response to analgesics ...... 193 Considerations for pain management in women ...... 193 Management of pain in neurologically handicapped persons ...... 194 Management of pain in the cognitively impaired elderly people ...... 194 Management of pain in brain-damaged minimally conscious patients ...... 195 Management of pain in the terminally ill ...... 195 Problems in the management of pain ...... 195 Inadequate pain management ...... 195 Problems with use of opioids ...... 196 Excessive prescription of gabapentinoids ...... 196 Problems with use of gabapentinoids ...... 197 Patterns of analgesic consumption in France vs other European countries ...... 197 Suggestions for improvement of pain management by healthcare providers ...... 197 Management of neuropathic pain refractory to first line treatment...... 199 Multidisciplinary approaches to pain management ...... 199 Pain as the fifth vital sign ...... 200 Reassessment of management of chronic pain ...... 200 Guidelines for the management of acute pain ...... 200

5. Drug Delivery for Pain ...... 202 Introduction ...... 202 Intra-articular injection for relief of joint pain ...... 203 Delivery of analgesics to peripheral nerves ...... 203 Controlled release drug delivery for pain ...... 204 Accelerating the effect of subcutaneous morphine ...... 204 Controlled drug delivery at site of pain ...... 204 Oral extended release opioids ...... 205 Extended release oral morphine ...... 205 Controlled release oxycodone ...... 205 Extended release oxymorphone ...... 205 Oral extended release tramadol ...... 206 Extended release gabapentin ...... 206 Use of nanotechnology for drug delivery for pain ...... 206 Non-injection methods of delivery of analgesics ...... 207 Topical applications for pain ...... 208 Topical local anesthetics ...... 208 Topical NSAIDs ...... 208 Topical and transdermal diclofenac ...... 209 Topical application for postoperative pain ...... 209 Needle-free drug delivery for pain ...... 209 Glide SDI® solid dose injector ...... 210 SUMAVEL™ DosePro™ needle-less injection ...... 210 Transdermal drug delivery for pain ...... 210 Relief of pain associated with minor medical procedures ...... 210 Transdermal fentanyl...... 211 Transdermal ketoprofen ...... 212 Transdermal nitroglycerine as an adjuvant to opioids ...... 212 Transdermal buprenorphine ...... 212 Transdermal trans-capsaicin ...... 213 Powder Injection Systems ...... 213 Intranasal delivery of analgesics ...... 214 Intranasal morphine ...... 214 Intranasal morphine derivatives ...... 214 Intranasal fentanyl ...... 215 Intranasal buprenorphine ...... 216 Intranasal ketamine ...... 216 Intranasal ketorolac ...... 216 Nasal formulations for migraine ...... 216 Oral spray formulations for migraine ...... 217 Delivery of analgesics by inhalation ...... 217 Buccal transmucosal and sublingual delivery of analgesics ...... 218 Application for cancer pain ...... 218 Application for non-cancer pain ...... 219 Pumps for drug delivery in pain ...... 219

- 8 - Patient controlled analgesia ...... 219 Postoperative pain pumps ...... 220 Chronogesic (sufentanil) Pain Therapy System...... 221 PatchPump ...... 221 Intrathecal delivery of analgesics ...... 222 Anatomical & physiological aspects of intrathecal drug delivery ...... 222 Pharmacokinetics of intrathecal drug delivery ...... 223 Epidural drugs ...... 224 Pharmacokinetics of analgesic drugs following epidural injection ...... 224 Epidural glucocorticoids ...... 224 Epidural etanercept ...... 224 Epidural morphine ...... 225 Intrathecal drugs ...... 225 Intrathecal adenosine ...... 226 Intrathecal baclofen ...... 227 Intrathecal fadolmidine ...... 227 Intrathecal lidocaine ...... 227 Intrathecal magnesium sulfate ...... 227 Intrathecal midazolam ...... 228 Intrathecal opioids ...... 228 Intrathecal neostigmine ...... 229 Intrathecal octeoride ...... 229 Intrathecal non-NMDA antagonists ...... 229 Intrathecal prostaglandin antagonists ...... 229 Intrathecal resiniferatoxin ...... 230 Intrathecal ziconotide ...... 230 Combinations of intrathecal agents for relief of pain ...... 231 Pumps for intrathecal delivery of analgesics ...... 231 Complications of intrathecal delivery of analgesics ...... 232 Concluding remarks on intrathecal delivery of analgesic agents ...... 232 Intracerebroventricular morphine for pain ...... 233 Development of drug delivery systems for pain therapy ...... 233 Delivery of analgesics to the CNS across the blood brain barrier ...... 233 Drug delivery systems in clinical trials ...... 234

6. Drug Development for Pain ...... 238 Introduction ...... 238 Current research goals ...... 238 An ideal analgesic ...... 238 Challenges and prospects of pain therapeutic development ...... 239 Priorities in pain research strategy in the US ...... 239 Pain R & D goals in the pharmaceutical industry ...... 240 Non-pharmacological therapies for pain ...... 240 Drugs in development for pain ...... 240 Drug targets in the spinal cord ...... 241 Drug targets in the brain ...... 241 Molecular targets for analgesic drugs ...... 242 Opioid peptide receptors ligands ...... 242 Opioid analgesics acting centrally ...... 243 Buprenorphine ...... 243 Cebranopadol ...... 243 Nociceptin ...... 243 Opioids with unique receptor characteristics ...... 244 Tapentadol ...... 244 Opioid analgesics acting outside the CNS ...... 244 Oliceridine ...... 244 Opioid analgesics acting at peripheral receptors ...... 245 Peripherally acting mu-opioid receptor agonists ...... 245 Targeting of opioid peptide-containing immune cells ...... 246 Advantages of peripherally selective opioid drugs ...... 246 Targets for non-opioid analgesics in development ...... 246 Activation of P2X7 receptors ...... 247 Alfa2-adrenergic receptor agonists ...... 248 Angiotensin II type 2 receptor ...... 248 Anti-NGF strategies ...... 248 Role of NGF in pain ...... 248 Biological approaches to targeting the NGF pathway ...... 249 Bradykinin antagonists ...... 249 Cannabinoids ...... 250 Cannabinoid receptor agonists ...... 250 Cannabidiol ...... 252

- 9 - Cannabinor ...... 253 Nabilone ...... 253 Capsaicin and VR1 receptor-based analgesics ...... 254 Vanilloid (capsaicin) receptor antagonists ...... 254 VR1 receptor agonists ...... 254 CCR2 receptor blockade ...... 254 Cholecystokinin antagonists ...... 255 Cholinergic receptor agonists ...... 255 Conotoxins as analgesics ...... 256 Corticotropin-releasing factor ...... 257 FAAH inhibitors ...... 257 PF-3845 ...... 257 URB597 ...... 258 FKBP51 as a target for treatment of chronic pain ...... 258 Free radical scavengers as analgesics ...... 258 Superoxide dismutase mimetics ...... 259 GABA analogs ...... 259 Subtype-selective GABAergic drugs ...... 259 Glutamate receptor antagonists ...... 259 NMDA receptor modulation for neuropathic pain ...... 260 Alternatives to direct blocking of NMDA receptors ...... 260 Glycine antagonists ...... 260 Metabotropic glutamate receptors ...... 261 Histogranin-like compounds for the management of pain ...... 261 Ion channels as targets for analgesic drugs ...... 262 Acid-sensing ion channels as drug target ...... 262 Calcium channel blockers ...... 262 HCN1 channels as targets for propofol analogs for neuropathic pain ...... 263 P2X ion channel receptor antagonists ...... 263 Sodium channel modulation ...... 264 Mas-related GPCR agonists...... 265 Microsomal prostaglandin E synthase inhibitors ...... 265 NAALADase inhibitors ...... 266 Neuropeptide receptor antagonists for improving the efficacy of opioids ...... 266 Neurotrophic factor-based pain therapeutics...... 266 Glial cell line-derived neurotrophic factor ...... 266 Nerve growth factor antagonists ...... 267 Newer COX inhibitors ...... 267 COX-3 inhibitors ...... 267 Dual cyclooxygenase/lipoxygenase inhibitors ...... 268 Nicotinic acetylcholine receptors ...... 268 Mode of action of nACh/neural nicotinic receptor agonists ...... 268 Potential of central nACh/neural nicotinic receptor agonists ...... 269 Nitric oxide-based analgesics ...... 269 Nitric oxide-releasing NSAIDs ...... 270 Pharmacology of NO-SAIDs ...... 270 COX-inhibiting nitric oxide donors ...... 271 NO-donating structures to extend life cycle of existing analgesics ...... 271 Nitric oxide mimetics ...... 271 Neuronal nitric oxide synthase inhibitors ...... 271 Norepinephrine transporter inhibition ...... 272 Resolvins ...... 272 Somatostatin analogs ...... 272 Substance P and neurokinin receptor antagonists ...... 273 Substance P-Saporin ...... 273 Targeting prostanoid synthesis ...... 274 Tetrodotoxin based analgesics ...... 274 TRPV1 modulators ...... 275 TRPV1 antagonists ...... 275 TRPV1 agonists ...... 276 TRPV1-mediated entry of sodium channel blocker QX-314...... 277 TRPV1 receptors regulate longevity ...... 277 Tumor necrosis factor- antagonists ...... 277 Biological therapies for pain ...... 278 Cell therapy for pain ...... 278 Cells for delivery of antinociceptive molecules ...... 279 Cell therapy for low back pain...... 279 Cell therapy for knee pain due to degenerative disorders ...... 280 Cell therapy for peripheral neuropathic pain ...... 280 Cell transplantation for relief of pain ...... 280 Transplantation of chromaffin cells ...... 280

- 10 - Transplantation of stem cells ...... 281 Transplantation of astrocytes secreting enkephalin ...... 281 Transplantation of cells for relief of neuropathic pain ...... 282 Concluding remarks on cell therapy for pain ...... 282 Gene therapy for pain ...... 283 Rationale of gene therapy for pain ...... 283 Gene therapy of peripheral neuropathy ...... 283 Gene therapy targeted to neuroimmune component of chronic pain ...... 284 Methods of gene delivery for pain ...... 284 Viral vector-mediated gene therapy of pain ...... 285 Vectors for endogenous analgesic production in cranial neuralgias ...... 285 Methods of gene delivery for pain ...... 286 Gene delivery by intrathecal route ...... 286 Gene transfer to the dorsal nerve roots ...... 286 Gene transfer by injections into the brain substance ...... 287 Antisense therapy for pain ...... 287 RNAi-based approaches for pain therapy ...... 288 Potential applications of gene therapy for management of pain ...... 289 Gene therapy for producing enkephalin to block pain signals ...... 289 Gene therapy for upregulation of BMP in backache ...... 291 Gene therapy for targeting nuclear factor-B ...... 291 Gene therapy for neuropathic pain ...... 291 Zinc finger DNA-binding protein therapeutic for chronic pain ...... 292 Concluding remarks about gene therapy for pain ...... 292 Preclinical development of pain drugs ...... 293 NGF-blocking antibody ...... 293 Prostatic acid phosphatase as a novel analgesic ...... 294 Preclinical development of drugs for neuropathic pain ...... 294 5-HT receptor agonists ...... 295 A-803467...... 295 α9α10 antagonists ...... 295 AM1241 ...... 296 Artemin/Neuroblastin ...... 296 Capsazepine ...... 297 Central nACh receptor agonists ...... 297 CGP 35024 ...... 297 Cortistatin ...... 298 Drugs that suppress glial activation ...... 298 Erythropoietin...... 299 NO donating GABA-agonist drugs ...... 299 Resiniferatoxin...... 299 Targeting tumor necrosis factor ...... 300 Future targets for osteoarthritic pain ...... 300 Pain drugs in clinical trials ...... 300 Clinical trials of miscellaneous drugs for pain ...... 300 Alvimopan ...... 302 Asimadoline ...... 303 EN3202 ...... 303 Oxytrex ...... 303 Drugs in clinical trials for postsurgical pain ...... 304 Bicifadine ...... 304 DepoMorphine ...... 305 Cox-2 inhibitors in clinical trials ...... 306 Clinical trials of disease modifying therapies for arthritis ...... 306 Drugs in clinical development for neuropathic pain ...... 308 Adenosine A1 agonists for neuropathic pain ...... 310 Ajulemic acid ...... 310 AVP-923 (dextromethorphan + quinidine) ...... 311 Botulinum toxin type A ...... 311 Carisbamate ...... 312 CNV1014802 ...... 312 D-amino acid oxidase inhibitors ...... 312 Glyx-13 ...... 312 IP-751 ...... 312 Lacosamide ...... 313 Oxcarbazepine ...... 313 Perampanel ...... 313 Ralfinamide ...... 313 Retigabine...... 314 SB-509 ...... 314 TC-6499 ...... 314

- 11 - Tebanicline ...... 314 Tezampanel ...... 315 Thalidomide ...... 315 TRO19622 ...... 315 V3381 (indantadol) ...... 316 XP-13512 ...... 316 Zonisamide ...... 316 Drug discovery and development for migraine ...... 317 Drugs in clinical development for treatment of migraine ...... 317 Clinical development of preventive therapies for migraine ...... 321 Monoclonal antibodies targeting CGRP for migraine prophylaxis ...... 321 Drug development for visceral pain ...... 322

7. Safety, Regulatory and Legal issues of pain management ...... 324 Safety issues of analgesics ...... 324 Adverse effects of analgesics ...... 324 Cardiovascular adverse effects of COX-2 inhibitors ...... 324 Gastrointestinal adverse effects of NSAIDs ...... 324 Measures to reduce gastrointestinal adverse effects of NSAIDs ...... 324 Adverse effects of opioids ...... 325 Addiction and development of tolerance ...... 325 Alternatives to opioids ...... 325 Buprenorphine as substitute for morphine addiction ...... 326 Chronic pain and opioid addiction ...... 326 Abuse-deterrant opioid products ...... 327 Problems and limitations of abuse-deterrant opioids ...... 329 Complications of opioid abuse in the elderly ...... 330 Hyperalgesia associated with opioids ...... 330 Narcotic bowel syndrome ...... 330 Opioid use disorder ...... 331 Opioid withdrawal ...... 331 Opioid-associated constipation ...... 332 Respiratory depression ...... 332 Guideline for use of opioids ...... 332 Opioid regulations ...... 333 Role of opioid prescribing patterns of physicians ...... 334 Use of opioids for chronic noncancer pain ...... 334 Adverse effects of use of opioids in noncancer pain ...... 334 Pharmacogenetics of adverse effects of codeine ...... 335 PEGylated naloxol ...... 335 Innovative approaches to modify opioid pharmacology ...... 336 Adverse effects of miscellaneous non-narcotic analgesics ...... 336 Adverse effects of immunosuppressants used for relief of pain ...... 336 Adverse effects of acetaminophen ...... 336 Hyponatremia as an adverse effect of tramadol ...... 336 Regulatory issues ...... 337 Opioids ...... 337 DEA and use of opioids for pain relief in terminal care ...... 337 Cannabinoids ...... 337 FDA and COX-2 inhibitors...... 338 Legal issues of COX-2 inhibitors ...... 338 Regulatory aspects of opioid safety and abuse ...... 339 Opioid misuse and regulatory agencies ...... 339 FDA measures for safety of opioid use ...... 339 Misuse of fentanyl ...... 341 Regulation of extended release and long-acting opioids ...... 341 Pain relief as a legal right ...... 342 Pain relief and the WHO ...... 342

8. Pain Markets ...... 344 Introduction ...... 344 Epidemiological basis of pain markets ...... 344 Cancer ...... 345 Neuropathic pain...... 345 Trigeminal neuralgia ...... 345 Arthritis ...... 345 Backache ...... 345 Migraine ...... 346 Multiple sclerosis ...... 346 Irritable bowel syndrome ...... 346 Chronic pelvic pain ...... 346

- 12 - Chronic pain due to traumatic brain injury ...... 346 Postsurgical pain ...... 347 Economics of pain ...... 347 Pain as a driver of healthcare costs ...... 347 Disability and financial loss through pain in the US ...... 348 Targeted delivery of analgesics for cancer pain ...... 348 Pain markets based on painful conditions ...... 348 The cancer pain market ...... 349 The arthritis pain market ...... 349 Postsurgical pain market ...... 350 The backache market ...... 350 The headache market ...... 350 Neuropathic pain market ...... 350 Fibromyalgia market ...... 351 Pain markets based on drugs ...... 351 Opioids ...... 352 Nonsteroidal antiinflammatory drugs ...... 352 Transdermal pain therapeutics ...... 353 Anesthesia ...... 353 Antiepileptic drugs as analgesics ...... 353 Other drugs...... 353 Hospital vs retail share of pain market ...... 353 Hospital versus retail opioid market ...... 354 Devices for pain ...... 354 Pain markets according to geographical areas ...... 354 Cost effectiveness of various approaches ...... 355 Unfulfilled R&D needs in pain therapy ...... 355 Under treatment of pain ...... 355 Unfulfilled needs in drug development for chronic pain ...... 355 Strategies for developing pain markets ...... 356 Finding alternatives to intrathecal administration for chronic pain ...... 357 Development of other applications of analgesic drugs ...... 357 Partnership of patients, pharmacists and companies ...... 357 Factors that may influence future pain markets ...... 358 Drivers of pain markets ...... 358 Public surveys as indicators of impact of pain on people ...... 358 Effect of regulatory reviews on markets for pain products ...... 359 Novel versus older therapies for pain ...... 359

9. Future of Pain Therapeutics ...... 360 Introduction ...... 360 Advances in the understanding of pain ...... 360 Pathogenesis of chronic pain ...... 360 Role of glia in neuropathic pain ...... 360 Molecular and neurobiological techniques ...... 361 Improved understanding of cancer pain ...... 362 Advances in drug discovery and development for pain ...... 362 Novel targets for drug discovery for pain ...... 362 PTH2 receptor ...... 362 Modulators of endogenous cannabinoids ...... 363 Application of new technologies to pain therapeutics ...... 363 Application of nanobiotechnology to pain therapeutics ...... 364 Technologies for the manufacture of analgesics ...... 365 Future trends and needs in pain management ...... 365 Pain management in future healthcare systems ...... 366 Systems biology approach to pain ...... 366 Personalized management of pain ...... 367 Genetic factors in response to pain...... 368 Genetic mutations with loss of pain ...... 369 Genetic mutations and painful conditions ...... 369 Mechanism-specific management of pain ...... 369 Gene expression biomarkers for personalizing pain management ...... 370 Pharmacogenomics and pharmacogenetics of pain ...... 370 Personalized management of pain with commonly used analgesics ...... 371 Personalized opioid therapy for noncancer pain ...... 371 Pharmacogenomics and pharmacogenetics of opioids ...... 371 Pharmacogenetics of COMT gene and pain ...... 372 Pharmacogenetics of NSAIDs and pain ...... 373 Preoperative testing to tailor postoperative analgesic requirements ...... 373 Prediction of response to an analgesic by in vitro iPSC based testing ...... 373 Role of conditioned pain modulation in personalized management of pain ...... 374

- 13 - Signature of pain on brain imaging ...... 374 Future of personalized pain management ...... 374 Strategies for improving pain management ...... 374 Research on pain in Europe ...... 375 Concluding remarks on future of pain management ...... 376

10. Companies Involved in Pain Therapeutics ...... 378 Introduction ...... 378 Profiles of companies...... 378 Collaborations ...... 559

11. References ...... 564

Tables

Table 1-1: Landmarks in the history of pain therapeutics ...... 21 Table 1-2: Classification of pain ...... 23 Table 1-3: Classification of neuropathic pain ...... 25 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: TRP channels involved in the regulation of pain and itch ...... 47 Table 1-7: Key molecular elements of pain in the peripheral nervous system ...... 55 Table 1-8: Key molecular elements of pain in the central nervous system ...... 55 Table 2-1: IASP guidelines for the use of animals in pain studies ...... 69 Table 2-2: Chronic pain as a manifestation of other diseases ...... 70 Table 2-3: Recommendations for assessing patient satisfaction with pain management ...... 76 Table 3-1: Classification of some currently used pain medications according to mechanism ...... 83 Table 3-2: Drugs used for the treatment of pain ...... 83 Table 3-3: Selective COX-2 inhibitors in clinical use for pain ...... 85 Table 3-4: Antiepileptic drugs with analgesic effect ...... 100 Table 4-1: Non-pharmacological approaches to management of pain ...... 111 Table 4-2: Companies involved in neuromodulation therapy for pain ...... 117 Table 4-3: Reasons for the inadequate management of acute pain ...... 121 Table 4-4:Monoclonal antibodies as disease modifying therapies in rheumatoid arthritis ...... 139 Table 4-5: Causes of chronic backache ...... 140 Table 4-6: Management of chronic pelvic pain ...... 144 Table 4-7: Management of pain in cancer ...... 145 Table 4-8: Definitions of tolerance, physiological dependence, withdrawal and addiction ...... 151 Table 4-9: A simplified classification of headache ...... 151 Table 4-10: Various methods for the management of acute migraine ...... 155 Table 4-11: Prophylaxis and management of chronic migraine ...... 159 Table 4-12: Evidence-based level of choice of drugs for prophylaxis of migraine ...... 162 Table 4-13: Management of neuropathic pain based on mechanism and diagnosis ...... 166 Table 4-14: Management of central neuropathic pain ...... 170 Table 4-15: Current management of peripheral diabetic neuropathy ...... 173 Table 4-16: Treatment strategies for postherpetic neuralgia...... 175 Table 4-17: Management of complex regional pain syndrome ...... 177 Table 4-18: Methods of treating phantom limb pain ...... 179 Table 4-19: Treatment of chronic unexplained pain due to central sensitization ...... 186 Table 4-20: Anti-itching therapies ...... 186 Table 4-21: Suggested improvements in the management of pain ...... 198 Table 5-1: A classification of drug delivery methods used in management of pain ...... 202 Table 5-2: Selected marketed non-injection drug delivery systems for pain ...... 207 Table 5-3: Approved drugs for spinal administration for pain ...... 225 Table 5-4: Off-label intrathecal use of drugs for for pain ...... 225 Table 5-5: Experimental studies of intrathecal administration of drugs for analgesia ...... 226 Table 5-6: Intrathecal drugs for pain in clinical trials ...... 226 Table 5-7: Comparison of pharmacokinetics of lipophilic with hydrophilic opioids ...... 228 Table 5-8: Delivery systems for pain (other than intrathecal) in clinical development ...... 235 Table 6-1: Classification of drugs in development for pain ...... 240 Table 6-2: Major opioids receptors and their ligands ...... 242 Table 6-3: Therapeutic targets for non-opioid analgesic drugs in development ...... 246 Table 6-4: Preclinical studies on cannabinoid (CB2) receptor agonists as analgesics ...... 251 Table 6-5: Cannabinoid receptor agonists in clinical development as analgesics ...... 252 Table 6-6: NO-related therapies for pain ...... 269 Table 6-7: Strategies to counteract pain at various levels at periphery and in the CNS ...... 274 Table 6-8: Types of TRPV1 antagonists ...... 276 Table 6-9: TRPV1 antagonists in clinical trials ...... 276 Table 6-10: Biological therapies for pain ...... 278

- 14 - Table 6-11: Experimental gene therapy approaches for relief of pain ...... 284 Table 6-12: Selected preclinical approaches to pain therapy ...... 293 Table 6-13: Selected preclinical drugs for neuropathic pain ...... 294 Table 6-14: Selected clinical trials of miscellaneous drugs for pain ...... 301 Table 6-15: Selected clinical trials of drugs for postsurgical pain ...... 304 Table 6-16: COX-2 inhibitors in clinical development ...... 306 Table 6-17: Disease modifying drugs for arthritis in clinical trials ...... 306 Table 6-18: Clinical trials of drugs for neuropathic pain ...... 308 Table 6-19: Selected drugs in clinical development for migraine ...... 317 Table 6-20: CGRP receptor antagonists in clinical development for acute migraine ...... 319 Table 6-21: Clinical trials of anti-CGRP monoclonal antibodies for migraine prevention ...... 322 Table 6-22: Therapeutic targets for treating visceral pain ...... 322 Table 7-1: Abuse-deterrant opioid products ...... 328 Table 7-2: Diagnostic criteria for an opioid-use disorder ...... 331 Table 8-1: Market values for various painful conditions 2020-2030 ...... 349 Table 8-2: Changes in market shares of drugs for neuropathic pain 2020-2030 ...... 351 Table 8-3: Markets for pain according to therapies 2020-2030 ...... 352 Table 8-4: Distribution of value of pain therapeutics in major markets 2020-2030 ...... 354 Table 8-5: Distribution of value of opioids in major pain markets 2020-2030...... 354 Table 8-6: Distribution of value of NSAIDs in major pain markets 2020-2030 ...... 355 Table 8-7: Strategies for developing pain markets ...... 356 Table 9-1: P450 isoforms in the metabolism of drugs used in the management of pain ...... 370 Table 10-1: Top companies in pain therapeutics ...... 378 Table 10-2: Product pipeline of Adolor Corporation ...... 385 Table 10-3: Selected collaborations in the area of pain management ...... 559

Figures

Figure 1-1: Afferent pain pathways ...... 30 Figure 1-2: Pain organ of the skin ...... 31 Figure 1-3: Evolution of the gate control theory ...... 33 Figure 1-4: The body self-neurometric...... 33 Figure 1-5: Various ligands and receptors on the peripheral terminals of nociceptive nerve fibers ...... 55 Figure 1-6: Prostaglandin biosynthesis pathway ...... 59 Figure 2-1: Biopsychosocial factors that interact and modulate the experience of pain...... 71 Figure 2-2: Pain intensity scales ...... 72 Figure 3-1: Sites of action of various methods of pain management ...... 82 Figure 3-2: Pathway of metabolism of codein ...... 91 Figure 4-1: The WHO step ladder for pain ...... 147 Figure 4-2: An algorithm for the acute management of migraine ...... 157 Figure 4-3: Neuroimmune activation events leading to sensitization of CNS ...... 165 Figure 4-4: An algorithm for the management of peripheral neuropathic pain ...... 178 Figure 4-5: Algorithm for management of patients with chronic pain and depression ...... 183 Figure 5-1: Powder Injection Systems ...... 213 Figure 5-2: Penetration of CSF into spinal cord ...... 222 Figure 5-3: Disposition of opioids after intrathecal administration ...... 224 Figure 6-1: Attributes of the ideal analgesic ...... 238 Figure 6-2: Role of NGF in pain...... 249 Figure 6-3: Nerve targeting drug delivery system for gene therapy of pain ...... 290 Figure 8-1: Unfulfilled needs in the treatment for chronic pain ...... 356 Figure 9-1: Impact of new technologies on pain therapeutics ...... 364 Figure 9-2: Essential components of personalized management of pain ...... 367 Figure 9-3: Personalized opioid therapy for noncancer pain ...... 371 Figure 9-4: Genetic and non-genetic factors affecting efficacy and side effects of opioids ...... 372

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