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Pain Therapeutics - Drugs, Markets and Companies

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  • 600 Pages
  • November 2021
  • Region: Global
  • Jain PharmaBiotech
  • ID: 4748158

This report describes the latest concepts of pathomechanisms of pain as a basis for the 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 anti-inflammatory drugs such as COX-2 inhibitors. Non-opioid analgesics include ketamine, an 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 as transdermal, pulmonary, and intranasal applications have been used. Topical analgesics and local anesthetics are also available. Devices such as implanted pumps are used for the 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 an 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 understanding of pain. Understanding the pathophysiology of pain is an important factor in the 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 173 of these are profiled in the report along with 156 collaborations. These are a mix of pharmaceutical companies and biotechnology companies.

The worldwide analgesic markets were analyzed for the year 2020 and projected to 2030. 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 78 tables, 25 figures, and 600 selected references to the literature.

The report contains information on the following:

  • Basic aspects of pain
  • Assessment of pain
  • Pharmacology of pain
  • Management of pain
  • Drug delivery for pain
  • Drug development for pain
  • Pain markets
  • Future of pain therapeutics
  • Companies involved pain therapeutics

Table of Contents

Executive Summary

1. Basic Aspects of Pain  

  • Introduction
  • Historical aspects of pain 
  • Pain definitions
  • A glossary of terms relevant to pain
  • Pain classification and description
  • Neuropathic pain
  • Refractory neuropathic pain
  • Classification of neuropathic pain according to levels 
  • Cancer pain
  • Bone pain in cancer
  • Complex regional pain syndrome 
  • Mechanisms of pain 
  • Pain pathways
  • Pain organ of the skin
  • Role of nociceptors in pain transmission
  • Gate control and neuromatrix theories of pain
  • Pain mediators  
  • Modulation of pain by pictures associated with social contacts 
  • Modulation of pain by emotions
  • Role of the sympathetic nervous system in pain 
  • Pathomechanism of inflammatory pain 
  • Pathomechanism of visceral pain 
  • Pathomechanism of neuropathic pain
  • Role of intact nerve fibers in neuropathic pain  
  • Chemokines as mediators of neuropathic pain  
  • Chemotherapy-induced neuropathic pain 
  • CNS innate immunity and neuropathic pain  
  • Cytokines as mediators of neuropathic pain  
  • Free radicals in the generation of neuropathic pain 
  • GABA deficiency in neuropathic pain
  • Genetic basis of neuropathic pain
  • Gene expression changes in neuropathic pain
  • Glial activation and neuropathic pain
  • Immune cell-derived opioids and neuropathic pain
  • Spinal leptin and neuropathic pain  
  • Tetrahydrobiopterin regulates neuropathic pain sensitivity 
  • Pathomechanism of migraine
  • Role of the immune system in pain  
  • Pain and itch 
  • Pathomechanism of itch 
  • Clinical aspects of itch
  • Molecular pathophysiology of pain
  • Role of ion channels in pain 
  • Acid-sensing ion channels  
  • Calcium channels in pain
  • P2X3 ion channels 
  • Potassium ion channels  
  • Sodium ion channels in pain
  • TRP ion channels in pain
  • Genetic basis of pain  
  • Alternative RNA splicing and pain
  • Study of genes in pain
  • Pain as a channelopathy
  • Pain in the brain
  • Effect of chronic pain on opioid receptors in the brain
  • Neuropathic pain-induced morphological changes in the brain
  • Change from acute to chronic pain
  • Acute versus chronic pain  
  • Descending facilitatory modulation of pain
  • Development of chronic pain following a severe accidental injury
  • Pain and transcriptional repressor DREAM
  • Role of neuronal plasticity in pain
  • Role of epigenetics in the development of chronic pain
  • Role of glial cells in chronic pain pathways
  • Concluding remarks on the evolution of acute pain into chronic pain 
  • Neurochemistry of pain
  • Molecular elements of pain in the peripheral nervous system  
  • Molecular elements of pain in the central nervous system  
  • Opioid receptors
  • Role of AMPA receptors in chronic pain
  • Kinins  
  • Serotonin 
  • Substance P 
  • Excitatory amino acids
  • Role of nitric oxide in pain  
  • Prostaglandins  
  • Endocannabinoids 
  • Protein kinase C
  • Adenosine and adenosine receptors 
  • Vitamin D and pain
  • Vanilloid receptor  
  • TRPA1 and TRPV1 receptors  
  • Endothelin-B receptors  
  • Nerve growth factor and pain 
  • Adrenomedullin as a pain-related peptide
  • Biomarkers of pain 
  • Biomarkers of visceral pain

2. Assessment of Pain and Analgesics

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

3. Pharmacotherapy of Pain

  • Introduction
  • Sites of action of various pain therapies  
  • Mechanism of action of currently used pain medications 
  • Non-steroidal anti-inflammatory drugs 
  • COX-2 inhibitors
  • Celecoxib 
  • Metamizole  
  • Nimesulide
  • Rofecoxib 
  • Valdecoxib
  • Lumiracoxib 
  • Side effects of COX inhibitors 
  • Innovative COX-2 inhibitors in development 
  • Acetaminophen  
  • Antioxidants as analgesics
  • Opiates and opioids 
  • Codeine
  • Morphine  
  • Morphine vs methadone  
  • Tramadol  
  • Innovations in opioid therapy  
  • Oral transmucosal fentanyl 
  • Use of opioids for chronic non-cancer pain
  • Opioid receptor modulation for visceral pain  
  • Opiorphin  
  • Sufentanil 
  • N-methyl-D-aspartate receptor antagonists
  • Ketamine  
  • CNS 5161 
  • Triptans for treatment of non-migrainous pain
  • Capsaicin 
  • NGX-4010 
  • Local anesthetics 
  • Topical application 
  • Nerve blocks 
  • Injection of local anesthetics for analgesia
  • Ultrasound-guided nerve blocks  
  • Topical salicylates for the treatment of pain
  • Topical rubefacients for acute and chronic pain in adults
  • Adjunctive analgesics  
  • Antidepressants 
  • Mechanism of analgesic action of antidepressants 
  • Antiepileptic drugs 
  • Mechanism of action of antiepileptic drugs in neuropathic pain
  • Carbamazepine 
  • Gabapentin  
  • Lamotrigine
  • Phenytoin  
  • Pregabalin  
  • Topiramate
  • Valproic acid
  • Other antiepileptic drugs  
  • Clonidine
  • Baclofen 
  • Corticosteroids  
  • Calcitonin
  • Bisphosphonates
  • Botulinum toxins
  • Analgesic effect of botulinum toxin A  
  • Engineered botulinum toxin
  • Analgesics from traditional medical systems 
  • Herbs and other plants 
  • Analgesics derived from cobra toxin

4. Management of Pain 

  • Introduction  
  • Sites for pain management
  • Self-medication at home
  • Physicians' offices
  • Major hospitals
  • Pain centers
  • Non-pharmacological approaches to pain  
  • Alternative medicine 
  • Acupuncture
  • Aromatherapy
  • Self-Controlled Energo Neuro Adaptive Regulation  
  • Behavioral therapy
  • Cognition and pain  
  • Control over brain activation and pain by using functional MRI 
  • Mindfulness meditation for relief of chronic pain  
  • Thermal-grill illusion
  • Virtual reality therapy  
  • Local application of heat
  • Transcutaneous nerve stimulation  
  • Non-invasive brain stimulation techniques for chronic pain.
  • Transcranial magnetic stimulation 
  • Cranial electrotherapy stimulation 
  • Neurosurgery for pain relief
  • Ablative procedures on the nervous system
  • Procedures on peripheral, spinal and cranial nerves 
  • Vagal nerve stimulation for control of pain 
  • Neuromodulation
  • Spinal cord stimulation
  • Brain stimulation
  • Implantation of drug delivery devices
  • Management of special types of pain 
  • Acute pain  
  • Management of acute renal colic: NSAIDS vs. opioids  
  • Combination of opioids and NSAIDs for acute pain  
  • Reasons for inadequate management of acute pain 
  • Perioperative pain management 
  • Devices for delivery of analgesics in the postoperative period
  • Drug combination for perioperative pain
  • Gabapentin for reduction of postoperative pain
  • Ketamine for perioperative pain
  • Opioids for perioperative pain
  • Perioperative pain in neurosurgery
  • Prolonged duration local anesthesia
  • Concluding remarks on the management of postoperative pain 
  • Pain in the intensive care unit
  • Pain associated with sports and exercise 
  • Pain associated with trauma  
  • Chronic pain and sleep 
  • Chronic abdominal pain
  • Functional somatic syndromes
  • Fibromyalgia syndrome 
  • Pathomechanism of FMS  
  • Management of FMS
  • Non-pharmacological therapies for FMS 
  • Pharmacotherapy of FMS 
  • Concluding remarks on management of FMS  
  • Erythromelalgia
  • Irritable bowel syndrome  
  • Opioids for IBS
  • Pregabalin for IBS
  • Tricyclic antidepressants for IBS
  • Serotonin-modulating drugs for IBS  
  • Musculoskeletal pain
  • Myofascial pain syndrome 
  • Non-pharmacological methods of treatment of MPS 
  • Pharmacotherapy of MPS 
  • Osteoarthritis  
  • Pain aggravates osteoarthritis by crosstalk between CNS and the joint  
  • Management of osteoarthritis
  • Rheumatoid arthritis 
  • Management of pain in rheumatoid arthritis
  • Disease modifying therapies in rheumatoid arthritis
  • Resurgence of interest in gold-based treatments for RA
  • Backache and sciatica
  • Lumbar disc disease and sciatica
  • Clinical trials of backache with sciatica
  • Management of back pain with analgesics  
  • Miscellaneous medical therapies for backache and sciatica
  • Neck pain
  • Chronic pelvic pain
  • Prostatitis  
  • Cancer pain 
  • Adjuvant drugs for cancer pain 
  • Alternative non-pharmacological methods  
  • Anesthetic techniques  
  • Management of bone pain in cancer  
  • Non-opioid analgesics for cancer pain
  • Opioid treatment of cancer pain
  • Opioid breakthrough pains
  • Opioid-induced enhancement of cancer growth and its prevention 
  • Opioids delivery methods for cancer pain
  • Opioid administration through implanted drug delivery devices 
  • Radiation therapy
  • Surgical methods of cancer pain relief
  • Conclusions regarding the management of cancer pain 
  • Chronic non-malignant pain  
  • Headache
  • Cluster headache
  • Chronic daily headache
  • Indomethacin-responsive headache
  • Occipital neuralgia  
  • Paroxysmal hemicrania
  • Post-traumatic headache 
  • Tension headache
  • Migraine 
  • Management of acute migraine 
  • Chronic migraine
  • Pediatric migraine
  • Status migrainosus 
  • Migraine prophylaxis
  • Non-pharmacological approaches to migraine 
  • Trigeminal neuralgia 
  • Dental pain 
  • Neuropathic pain 
  • Pathogenesis of neuropathic pain  
  • Chronobiology of neuropathic pain as guide to therapy
  • Management of neuropathic pain based on mechanism
  • Guidelines for the management of neuropathic pain
  • Pharmacotherapy of neuropathic pain
  • Evidence-based management of neuropathic pain
  • Management of central neuropathic pain 
  • Neurosurgical approaches to central neuropathic pain 
  • Management of neuropathic pain in syringomyelia  
  • Neuropathic pain associated with spinal cord injury 
  • Management of peripheral neuropathic pain
  • Truncal neuropathic pain  
  • Management of postsurgical peripheral neuropathic pain 
  • Management of chemotherapy-induced pain
  • Morton’s neuroma
  • Management of peripheral diabetic neuropathy
  • Postherpetic neuralgia 
  • Treatment of complex regional pain syndrome
  • An algorithm for the management of peripheral neuropathic pain 
  • Phantom limb pain
  • Pathomechanism of phantom limb pain  
  • Management of phantom limb pain
  • Painful neuromas following amputation
  • Pain and depression 
  • Neurochemical link between pain and depression
  • Management of chronic pain and depression  
  • Miscellaneous painful conditions 
  • Burning mouth syndrome 
  • Chronic unstable angina
  • Mastalgia
  • Ophthalmic pain 
  • Pain in Parkinson's disease
  • Pain in sickle cell disease  
  • Management of chronic unexplained pain
  • Management of itching 
  • Topical applications for itching  
  • Systemic therapies for itching
  • Non-pharmacological therapies for itch  
  • Management of pain in special population groups 
  • Racial and ethnic differences in pain management
  • Pain in neonates  
  • Management of pain in children 
  • Misuse of codeine in children
  • Management of pain in the elderly 
  • Management of pain in women  
  • Reasons for increased pain perception in women
  • Chronic pelvic pain in women
  • Gender differences in response to analgesics  
  • Considerations for pain management in women  
  • Management of pain in neurologically handicapped persons  
  • Management of pain in the cognitively impaired elderly people  
  • Management of pain in brain-damaged minimally conscious patients  
  • Management of pain in the terminally ill 
  • Problems in the management of pain
  • Inadequate pain management
  • Problems with the use of opioids 
  • Excessive prescription of gabapentinoids 
  • Problems with the use of gabapentinoids 
  • Patterns of analgesic consumption in France vs other European countries
  • Suggestions for improvement of pain management by healthcare providers
  • Management of neuropathic pain refractory to first line treatment
  • Multidisciplinary approaches to pain management
  • Pain as the fifth vital sign 
  • Reassessment of management of chronic pain
  • Guidelines for the management of acute pain 

5. Drug Delivery for Pain  

  • Introduction  
  • Intra-articular injection for relief of joint pain
  • Delivery of analgesics to peripheral nerves
  • Controlled release drug delivery for pain
  • Accelerating the effect of subcutaneous morphine
  • Controlled drug delivery at the site of pain
  • Oral extended release opioids
  • Extended release oral morphine
  • Controlled release oxycodone
  • Extended release oxymorphone
  • Oral extended release tramadol
  • Extended release gabapentin 
  • Use of nanotechnology for drug delivery for pain 
  • Non-injection methods of delivery of analgesics
  • Topical applications for pain  
  • Topical local anesthetics  
  • Topical NSAIDs
  • Topical and transdermal diclofenac
  • Topical application for postoperative pain
  • Needle-free drug delivery for pain  
  • Glide SDI® solid dose injector  
  • SUMAVEL™ DosePro™ needle-less injection
  • Transdermal drug delivery for pain 
  • Relief of pain associated with minor medical procedures  
  • Transdermal fentanyl. 
  • Transdermal ketoprofen
  • Transdermal nitroglycerine as an adjuvant to opioids  
  • Transdermal buprenorphine 
  • Transdermal trans-capsaicin 
  • Powder Injection Systems
  • Intranasal delivery of analgesics
  • Intranasal morphine
  • Intranasal morphine derivatives
  • Intranasal fentanyl  
  • Intranasal buprenorphine 
  • Intranasal ketamine
  • Intranasal ketorolac
  • Nasal formulations for migraine
  • Oral spray formulations for migraine  
  • Delivery of analgesics by inhalation
  • Buccal transmucosal and sublingual delivery of analgesics
  • Application for cancer pain
  • Application for non-cancer pain 
  • Pumps for drug delivery in pain 
  • Patient controlled analgesia  
  • Postoperative pain pumps
  • Chronogesic (sufentanil) Pain Therapy System
  • PatchPump 
  • Intrathecal delivery of analgesics  
  • Anatomical & physiological aspects of intrathecal drug delivery  
  • Pharmacokinetics of intrathecal drug delivery  
  • Epidural drugs 
  • Pharmacokinetics of analgesic drugs following epidural injection
  • Epidural glucocorticoids
  • Epidural etanercept 
  • Epidural morphine
  • Intrathecal drugs 
  • Intrathecal adenosine  
  • Intrathecal baclofen
  • Intrathecal fadolmidine
  • Intrathecal lidocaine
  • Intrathecal magnesium sulfate 
  • Intrathecal midazolam 
  • Intrathecal opioids  
  • Intrathecal neostigmine
  • Intrathecal octeoride
  • Intrathecal non-NMDA antagonists
  • Intrathecal prostaglandin antagonists
  • Intrathecal resiniferatoxin
  • Intrathecal ziconotide  
  • Combinations of intrathecal agents for relief of pain 
  • Pumps for intrathecal delivery of analgesics
  • Complications of intrathecal delivery of analgesics
  • Concluding remarks on intrathecal delivery of analgesic agents 
  • Intracerebroventricular morphine for pain
  • Development of drug delivery systems for pain therapy
  • Delivery of analgesics to the CNS across the blood brain barrier
  • Drug delivery systems in clinical trials

6. Drug Development for Pain

  • Introduction  
  • Current research goals  
  • An ideal analgesic
  • Challenges and prospects of pain therapeutic development
  • Priorities in pain research strategy in the US
  • Pain R & D goals in the pharmaceutical industry  
  • Non-pharmacological therapies for pain  
  • Drugs in development for pain
  • Drug targets in the spinal cord  
  • Drug targets in the brain
  • Molecular targets for analgesic drugs
  • Opioid peptide receptors ligands
  • Opioid analgesics acting centrally
  • Buprenorphine
  • Cebranopadol 
  • Nociceptin  
  • Opioids with unique receptor characteristics
  • Tapentadol 
  • Opioid analgesics acting outside the CNS
  • Oliceridine  
  • Opioid analgesics acting at peripheral receptors  
  • Peripherally acting mu-opioid receptor agonists  
  • Targeting of opioid peptide-containing immune cells
  • Advantages of peripherally selective opioid drugs
  • Targets for non-opioid analgesics in development
  • Activation of P2X7 receptors  
  • Alfa2-adrenergic receptor agonists 
  • Angiotensin II type 2 receptor
  • Anti-NGF strategies  
  • Role of NGF in pain 
  • Biological approaches to targeting the NGF pathway
  • Bradykinin antagonists 
  • Cannabinoids
  • Cannabinoid receptor agonists  
  • Cannabidiol
  • Cannabinor
  • Nabilone
  • Capsaicin and VR1 receptor-based analgesics  
  • Vanilloid (capsaicin) receptor antagonists
  • VR1 receptor agonists 
  • CCR2 receptor blockade
  • Cholecystokinin antagonists  
  • Cholinergic receptor agonists 
  • Conotoxins as analgesics  
  • Corticotropin-releasing factor
  • FAAH inhibitors
  • PF-3845 
  • URB597 
  • FKBP51 as a target for the treatment of chronic pain 
  • Free radical scavengers as analgesics 
  • Superoxide dismutase mimetics
  • GABA analogs  
  • Subtype-selective GABAergic drugs
  • Glutamate receptor antagonists 
  • NMDA receptor modulation for neuropathic pain 
  • Alternatives to direct blocking of NMDA receptors
  • Glycine antagonists 
  • Metabotropic glutamate receptors 
  • Histogranin-like compounds for the management of pain  
  • Ion channels as targets for analgesic drugs 
  • Acid-sensing ion channels as a drug target
  • Calcium channel blockers 
  • HCN1 channels as targets for propofol analogs for neuropathic pain  
  • P2X ion channel receptor antagonists
  • Sodium channel modulation 
  • Mas-related GPCR agonists
  • Microsomal prostaglandin E synthase inhibitors
  • NAALADase inhibitors
  • Neuropeptide receptor antagonists for improving the efficacy of opioids  
  • Neurotrophic factor-based pain therapeutics
  • Glial cell line-derived neurotrophic factor
  • Nerve growth factor antagonists
  • Newer COX inhibitors
  • COX-3 inhibitors 
  • Dual cyclooxygenase/lipoxygenase inhibitors  
  • Nicotinic acetylcholine receptors
  • Mode of action of nACh/neural nicotinic receptor agonists
  • Potential of central nACh/neural nicotinic receptor agonists  
  • Nitric oxide-based analgesics 
  • Nitric oxide-releasing NSAIDs
  • Pharmacology of NO-SAIDs  
  • COX-inhibiting nitric oxide donors 
  • NO-donating structures to extend life cycle of existing analgesics 
  • Nitric oxide mimetics
  • Neuronal nitric oxide synthase inhibitors
  • Norepinephrine transporter inhibition 
  • Resolvins
  • Somatostatin analogs
  • Substance P and neurokinin receptor antagonists 
  • Substance P-Saporin
  • Targeting prostanoid synthesis  
  • Tetrodotoxin based analgesics
  • TRPV1 modulators
  • TRPV1 antagonists  
  • TRPV1 agonists
  • TRPV1-mediated entry of sodium channel blocker QX-314
  • TRPV1 receptors regulate longevity
  • Tumor necrosis factor- antagonists
  • Biological therapies for pain  
  • Cell therapy for pain  
  • Cells for delivery of antinociceptive molecules 
  • Cell therapy for low back pain
  • Cell therapy for knee pain due to degenerative disorders  
  • Cell therapy for peripheral neuropathic pain
  • Cell transplantation for relief of pain
  • Transplantation of chromaffin cells
  • Transplantation of stem cells
  • Transplantation of astrocytes secreting enkephalin  
  • Transplantation of cells for relief of neuropathic pain
  • Concluding remarks on cell therapy for pain
  • Gene therapy for pain
  • Rationale of gene therapy for pain 
  • Gene therapy of peripheral neuropathy  
  • Gene therapy targeted to neuroimmune component of chronic pain  
  • Methods of gene delivery for pain  
  • Viral vector-mediated gene therapy of pain 
  • Vectors for endogenous analgesic production in cranial neuralgias
  • Methods of gene delivery for pain  
  • Gene delivery by intrathecal route
  • Gene transfer to the dorsal nerve roots 
  • Gene transfer by injections into the brain substance
  • Antisense therapy for pain
  • RNAi-based approaches for pain therapy 
  • Potential applications of gene therapy for the management of pain  
  • Gene therapy for producing enkephalin to block pain signals
  • Gene therapy for upregulation of BMP in backache  
  • Gene therapy for targeting nuclear factor-B  
  • Gene therapy for neuropathic pain
  • Zinc finger DNA-binding protein therapeutic for chronic pain
  • Concluding remarks about gene therapy for pain 
  • Preclinical development of pain drugs
  • NGF-blocking antibody  
  • Prostatic acid phosphatase as a novel analgesic
  • Preclinical development of drugs for neuropathic pain
  • 5-HT receptor agonists
  • A-803467. 
  • α9α10 antagonists  
  • AM1241 
  • Artemin/Neuroblastin  
  • Capsazepine
  • Central nACh receptor agonists 
  • CGP 35024 
  • Cortistatin  
  • Drugs that suppress glial activation
  • Erythropoietin... 
  • NO donating GABA-agonist drugs  
  • Resiniferatoxin.. 
  • Targeting tumor necrosis factor
  • Future targets for osteoarthritic pain  
  • Pain drugs in clinical trials 
  • Clinical trials of miscellaneous drugs for pain
  • Alvimopan  
  • Asimadoline
  • EN3202 
  • Oxytrex 
  • Drugs in clinical trials for postsurgical pain  
  • Bicifadine
  • DepoMorphine
  • Cox-2 inhibitors in clinical trials 
  • Clinical trials of disease modifying therapies for arthritis
  • Drugs in clinical development for neuropathic pain
  • Adenosine A1 agonists for neuropathic pain
  • Ajulemic acid  
  • AVP-923 (dextromethorphan + quinidine)  
  • Botulinum toxin type A
  • Carisbamate
  • CNV1014802  
  • D-amino acid oxidase inhibitors
  • Glyx-13 
  • IP-751
  • Lacosamide
  • Oxcarbazepine
  • Perampanel
  • Ralfinamide
  • Retigabine 
  • SB-509  
  • TC-6499
  • Tebanicline 
  • Tezampanel
  • Thalidomide
  • TRO19622  
  • V3381 (indantadol) 
  • XP-13512
  • Zonisamide
  • Drug discovery and development for migraine 
  • Drugs in clinical development for the treatment of migraine
  • Clinical development of preventive therapies for migraine
  • Monoclonal antibodies targeting CGRP for migraine prophylaxis
  • Drug development for visceral pain

7. Safety, Regulatory and Legal issues of pain management

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

8. Pain Markets 

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

9. Future of Pain Therapeutics  

  • Introduction  
  • Advances in the understanding of pain  
  • Pathogenesis of chronic pain 
  • Role of glia in neuropathic pain  
  • Molecular and neurobiological techniques
  • Improved understanding of cancer pain  
  • Advances in drug discovery and development for pain  
  • Novel targets for drug discovery for pain
  • PTH2 receptor
  • Modulators of endogenous cannabinoids
  • Application of new technologies to pain therapeutics
  • Application of nanobiotechnology to pain therapeutics 
  • Technologies for the manufacture of analgesics  
  • Future trends and needs in pain management
  • Pain management in future healthcare systems
  • Systems biology approach to pain 
  • Personalized management of pain 
  • Genetic factors in response to pain
  • Genetic mutations with loss of pain
  • Genetic mutations and painful conditions
  • Mechanism-specific management of pain
  • Gene expression biomarkers for personalizing pain management
  • Pharmacogenomics and pharmacogenetics of pain
  • Personalized management of pain with commonly used analgesics 
  • Personalized opioid therapy for noncancer pain
  • Pharmacogenomics and pharmacogenetics of opioids  
  • Pharmacogenetics of COMT gene and pain 
  • Pharmacogenetics of NSAIDs and pain
  • Preoperative testing to tailor postoperative analgesic requirements
  • Prediction of response to an analgesic by in vitro iPSC based testing  
  • Role of conditioned pain modulation in personalized management of pain
  • Signature of pain on brain imaging 
  • Future of personalized pain management
  • Strategies for improving pain management
  • Research on pain in Europe
  • Concluding remarks on future of pain management  

10. Companies Involved in Pain Therapeutics 

  • Introduction  
  • Profiles of companies
  • Collaborations

11. References
Table 1-1: Landmarks in the history of pain therapeutics  
Table 1-2: Classification of pain 
Table 1-3: Classification of neuropathic pain
Table 1-4: Classification of chronic cancer pain according to cause... 
Table 1-5: Percentage of patients with pain according to the type of cancer
Table 1-6: TRP channels involved in the regulation of pain and itch
Table 1-7: Key molecular elements of pain in the peripheral nervous system  
Table 1-8: Key molecular elements of pain in the central nervous system
Table 2-1: IASP guidelines for the use of animals in pain studies
Table 2-2: Chronic pain as a manifestation of other diseases 
Table 2-3: Recommendations for assessing patient satisfaction with pain management
Table 3-1: Classification of some currently used pain medications according to mechanism
Table 3-2: Drugs used for the treatment of pain  
Table 3-3: Selective COX-2 inhibitors in clinical use for pain  
Table 3-4: Antiepileptic drugs with analgesic effect  
Table 4-1: Non-pharmacological approaches to management of pain
Table 4-2: Companies involved in neuromodulation therapy for pain
Table 4-3: Reasons for the inadequate management of acute pain
Table 4-4:Monoclonal antibodies as disease modifying therapies in rheumatoid arthritis 
Table 4-5: Causes of chronic backache 
Table 4-6: Management of chronic pelvic pain
Table 4-7: Management of pain in cancer 
Table 4-8: Definitions of tolerance, physiological dependence, withdrawal and addiction 
Table 4-9: A simplified classification of headache
Table 4-10: Various methods for the management of acute migraine
Table 4-11: Prophylaxis and management of chronic migraine
Table 4-12: Evidence-based level of choice of drugs for prophylaxis of migraine
Table 4-13: Management of neuropathic pain based on mechanism and diagnosis 
Table 4-14: Management of central neuropathic pain 
Table 4-15: Current management of peripheral diabetic neuropathy
Table 4-16: Treatment strategies for postherpetic neuralgia
Table 4-17: Management of complex regional pain syndrome  
Table 4-18: Methods of treating phantom limb pain
Table 4-19: Treatment of chronic unexplained pain due to central sensitization 
Table 4-20: Anti-itching therapies
Table 4-21: Suggested improvements in the management of pain
Table 5-1: A classification of drug delivery methods used in the management of pain  
Table 5-2: Selected marketed non-injection drug delivery systems for pain  
Table 5-3: Approved drugs for spinal administration for pain
Table 5-4: Off-label intrathecal use of drugs for pain 
Table 5-5: Experimental studies of intrathecal administration of drugs for analgesia  
Table 5-6: Intrathecal drugs for pain in clinical trials  
Table 5-7: Comparison of pharmacokinetics of lipophilic with hydrophilic opioids
Table 5-8: Delivery systems for pain (other than intrathecal) in clinical development 
Table 6-1: Classification of drugs in development for pain
Table 6-2: Major opioids receptors and their ligands  
Table 6-3: Therapeutic targets for non-opioid analgesic drugs in development  
Table 6-4: Preclinical studies on cannabinoid (CB2) receptor agonists as analgesics
Table 6-5: Cannabinoid receptor agonists in clinical development as analgesics 
Table 6-6: NO-related therapies for pain
Table 6-7: Strategies to counteract pain at various levels at periphery and in the CNS
Table 6-8: Types of TRPV1 antagonists 
Table 6-9: TRPV1 antagonists in clinical trials
Table 6-10: Biological therapies for pain
Table 6-11: Experimental gene therapy approaches for relief of pain
Table 6-12: Selected preclinical approaches to pain therapy
Table 6-13: Selected preclinical drugs for neuropathic pain 
Table 6-14: Selected clinical trials of miscellaneous drugs for pain
Table 6-15: Selected clinical trials of drugs for postsurgical pain  
Table 6-16: COX-2 inhibitors in clinical development  
Table 6-17: Disease modifying drugs for arthritis in clinical trials 
Table 6-18: Clinical trials of drugs for neuropathic pain  
Table 6-19: Selected drugs in clinical development for migraine  
Table 6-20: CGRP receptor antagonists in clinical development for acute migraine 
Table 6-21: Clinical trials of anti-CGRP monoclonal antibodies for migraine prevention
Table 6-22: Therapeutic targets for treating visceral pain
Table 7-1: Abuse-deterrant opioid products  
Table 7-2: Diagnostic criteria for an opioid-use disorder 
Table 8-1: Market values for various painful conditions 2020-2030  
Table 8-2: Changes in market shares of drugs for neuropathic pain 2020-2030 
Table 8-3: Markets for pain according to therapies 2020-2030
Table 8-4: Distribution of value of pain therapeutics in major markets 2020-2030 
Table 8-5: Distribution of value of opioids in major pain markets 2020-2030... 
Table 8-6: Distribution of value of NSAIDs in major pain markets 2020-2030
Table 8-7: Strategies for developing pain markets 
Table 9-1: P450 isoforms in the metabolism of drugs used in the management of pain
Table 10-1: Top companies in pain therapeutics
Table 10-2: Product pipeline of Adolor Corporation
Table 10-3: Selected collaborations in the area of pain management

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