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Pain Therapeutics - Drugs, Markets and Companies

  • ID: 4748158
  • Report
  • December 2019
  • Region: Global
  • 597 Pages
  • Jain PharmaBiotech
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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, 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 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 the 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 2018 and projected to 2028. 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 76 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
Note: Product cover images may vary from those shown
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0. 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 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 severe accidental injury
Pain and transcriptional repressor DREAM  
Role of neuronal plasticity in pain
Role of epigenetics in development of chronic pain
Concluding remarks on 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 study of pain
PET for 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 study of chronic pain
Placebo effect in pain  
Role of electronic pain recording in 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 antiinflammatory 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 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 use of opioids  
Excessive prescription of gabapentinoids
Problems with 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

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 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  
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 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 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  
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
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  
Vectors for 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 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 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 substitute for morphine addiction  
Chronic pain and opioid addiction
Abuse-deterrant opioid products  
Problems and limitations of abuse-deterrant 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 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 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

Tables
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: Key molecular elements of pain in the peripheral nervous system  
Table 1-7: 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 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 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: Preclinical studies on cannabinoid (CB2) receptor agonists as analgesics  
Table 6-3: Cannabinoid receptor agonists in clinical development as analgesics
Table 6-4: NO-related therapies for pain
Table 6-5: Major opioids receptors and their ligands  
Table 6-6: Strategies to counteract pain at various levels at periphery and in the CNS  
Table 6-7: Types of TRPV1 antagonists
Table 6-8: TRPV1 antagonists in clinical trials
Table 6-9: Biological therapies for pain
Table 6-10: Experimental gene therapy approaches for relief of pain
Table 6-11: Selected preclinical approaches to pain therapy
Table 6-12: Selected preclinical drugs for neuropathic pain
Table 6-13: Selected clinical trials of miscellaneous drugs for pain  
Table 6-14: Selected clinical trials of drugs for postsurgical pain
Table 6-15: COX-2 inhibitors in clinical development
Table 6-16: Disease modifying drugs for arthritis in clinical trials  
Table 6-17: Clinical trials of drugs for neuropathic pain  
Table 6-18: Selected drugs in clinical development for migraine  
Table 6-19: CGRP receptor antagonists in clinical development for acute migraine
Table 6-20: Clinical trials of anti-CGRP monoclonal antibodies for migraine prevention  
Table 6-21: 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 2018-2028  
Table 8-2: Changes in market shares of drugs for neuropathic pain 2018-2028
Table 8-3: Markets for pain according to therapies 2018-2028  
Table 8-4: Distribution of value of pain therapeutics in major markets 2018-2028  
Table 8-5: Distribution of value of opioids in major pain markets 2018-2028
Table 8-6: Distribution of value of NSAIDs in major pain markets 2018-2028
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  

Figures
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

Note: Product cover images may vary from those shown
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