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Pain Therapeutics - Drugs, Markets and Companies

  • ID: 4748158
  • Report
  • 594 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 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 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, 24 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 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 management of cancer pain
Chronic non-malignant pain  
Headache  
Cluster headache  
Chronic daily headache  
Indomethacin-responsive headache
Occipital neuralgia  
Paroxysmal hemicrania  
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 itching 
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
Buprenorphine as substitute for morphine addiction  
Guideline for use of opioids  
Opioid regulations
Opioids alternatives
Post-operative 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
Gastrointestinal adverse effects of NSAIDs  
Measures to reduce gastrointestinal adverse effects of NSAIDs
Cardiovascular adverse effects of COX-2 inhibitors
Adverse effects of opioids
Addiction and development of tolerance
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  
Role of opioid prescribing patterns of physicians  
Adverse effects of use of opioids in non-malignant 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 anti-inflammatory 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  
Pharmacogenomics and pharmacogenetics of pain
Personalized management of pain with commonly used analgesics
Pharmacogenomics and pharmacogenetics of opioids  
Pharmacogenetics of NSAIDs  
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 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: 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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